Compositions and methods for reducing overdose

ABSTRACT

Drug delivery formulations, uses thereof and methods of making same are provided in order to reduce the potential for abuse, misuse or improper administration of an addictive substance or any active substance and to prevent, reduce, inhibit, or delay purposeful or accidental overdose of an active substance by ingesting too many dosage forms at once, for example.

FIELD OF THE INVENTION

The present invention relates to compositions and methods for reducingoverdose and reducing drug abuse, in particular to compositions,methods, uses thereof, and methods for making same.

BACKGROUND

Substance abuse, also known as drug abuse, is a patterned use of asubstance in which the user consumes the substance in amounts or usesmethods with these substances which are harmful to themselves or others.A well known and documented form of substance abuse, especially in theuse of opioid analgesics, is that involving the deliberate crushing,snorting or injecting of solid oral medication intended to be takenintact in order to get a feeling of euphoria.

Almost all of the abuse-deterrent formulations currently known are aimedat preventing patients from crushing, snorting, or injecting them. Whilethese are very high-risk behaviours, they likely represent a smallminority of patients who abuse prescribed opioids. Most patients who areabusing opioids are likely taking more than prescribed by mouth, orcombining them with other medications and drugs.

The Food and Drug Administration (FDA) corroborates this observation.According to this regulatory agency, “opioid analgesics are oftenmanipulated for purposes of abuse. Most abuse-deterrent technologiesdeveloped to date are designed to make product manipulation moredifficult or to make abuse of the manipulated product less attractive orrewarding. However, these technologies have not yet proven successful atdeterring the most common form of abuse—swallowing a number of intactpills or tablets to achieve a feeling of euphoria.” (see FDA DraftGuidance for Industry title Abuse-Deterrent Opioids—Evaluation andLabeling of January 2013).

Substance abuse can lead to addiction, serious adverse events, or insome cases, overdose and death. Overdose and death can also result frommistaken or intentional oral ingestion of a number of intactpharmaceutical unit dosage formulations, such as pills.

Drug overdose is the leading cause of accidental death in the UnitedStates, causing more deaths than motor vehicle crashes in 2010 amongpeople 25 to 64 years old. It is now generally accepted that the leadingcause of death in drug overdoses in the U.S. today is prescriptiondrugs. Drug overdose death rates have been rising steadily since 1992with a 102% increase from 1999 to 2010 alone.

A major issue of great concern is that there continues to be reports ofpeople deliberately or mistakenly swallowing a number of intact pills ortablets despite instructions not to do so, and suffering serious adverseeffects as a result. Products containing active ingredients that willproduce an emotional, psychological, euphoric, depressive, or generallypsychedelic experience are particularly vulnerable to this form ofabuse.

Attempts have been made in the past to control abuse or overdose fromswallowing a number of intact solid dosage forms, but formulations andmethods currently taught have not successfully prevented overdose fromswallowing a number of intact tablets or capsules. Some of theseapproaches are sometimes executed after the fact, i.e., directed at arescue therapy after overdose has occurred and do not necessarilyaddress the issue of preventing overdose from occurring in the firstplace.

U.S. Pat. Nos. 7,375,083 and 8,106,016 relate to pharmaceuticalcompositions comprised of a chemical moiety attached to an active agentin a manner that substantially decreases the potential of the activeagent to cause overdose or to be abused. When delivered at the properdosage the pharmaceutical composition provides therapeutic activitysimilar to that of the parent active agent.

U.S. Pat. No. 5,474,757 relates to a method of preventing acetaminophen(APAP)-induced hepatotoxicity utilizing diallyl sulfide (DAS) anddiallyl sulfone (DASO₂). DAS and DASO₂ are prepared as an oral dosageform or injected. In a preferred embodiment, diallyl sulfone is added toa dosage form of acetaminophen in an amount effective to prevent themetabolism of said unit dose of acetaminophen into its hepatotoxicmetabolites. In certain preferred embodiments, the above formulationsfurther include an effective amount of N-acetylcysteine to detoxifyhepatotoxic metabolites of acetaminophen.

U.S. Pat. No. 6,604,650 relates to a medicine-dispensing system having amedication reminder to assist the patient in following a drug regimen.In an example embodiment, a medication reminder comprises a timerprogrammable to a predetermined interval. A user-alert is responsive tothe timer, reminding the user to take a dose of medicine at thepredetermined interval. A sensor detects whether a dose of medicine hasbeen taken and a dose-indication informs the user of the time since alast medication. The dose indication further informs the user as towhether to take a next medication dose. Time of the last dose isdetermined by the timer receiving a signal from the sensor. Acommunications interface enables programming of a parameter associatedwith administering a medication.

U.S. Pat. No. 7,295,890 relates to a drug compliance monitoring systemthat provides a patient with a portable medication dispenser programmedwith medication-taking data. The dispenser alerts the patient to take adose of medication and gathers compliance data relating to themedication-taking data. The compliance data is accessible to aphysician, or other care givers, etc., via a network database.

U.S. Pat. No. 5,643,560 relates to the use of, and methods to obtain,ion exchanger complexes with psychotropic drugs for reducing toxic sideeffects and lethality when overdosing the drug. The invention includesmethods and compositions for modifying the total amount of drug releasedfrom the complex in the gastro-intestinal tract by adding a substancewhich affects the ion exchange process. The additional substance may bea salt which generates an ion with higher or similar affinity to the ionexchanger when compared to the drug. The additional substance may be acounter ion in an additional complex with an ion exchanger.

U.S. Patent Application Publication No. 2013/0034503 relates to a methodand composition for treating a patient that prevents or reduces drugabuse and overdose events with drugs. The method comprises: oraladministration of a pharmaceutical composition comprising at least onedrug bound to at least one ion exchange resin as a resinate, said ionexchange resins being selected from the group consisting of a cationicion exchange resin and a anionic ion exchange resin, each said ionexchange resin being bound to at least one drug, wherein each said bounddrug, measured as the unbound state, is less than about 75 percent ofits saturation concentration in its resinate.

Australian Patent No. 769952 relates to an orally administrablepharmaceutical product comprising an information carrier having a formand composition such that information is recorded by the carrier;wherein the information carrier comprises a resistant material that isresistant to the gastric environment. The presence of the informationcarrier facilitates the treatment of overdose patients who have consumedlarge quantities of the pharmaceutical product. The information mayrelate to the characteristics of the product and may be recorded byengraving characters into the information carrier.

U.S. Pat. No. 3,254,088 relates to the preparation of naloxone and itsactivity as a narcotic antagonist. U.S. Pat. No. 3,493,657 relates tothe combination of morphine and naloxone as a composition for parenteraluse “which has a strong analgesic, as well as antagonistic effect,without the occurrence of undesired or dangerous side effects.”

The combination of pentazocine and naloxone has been utilized in tabletsavailable in the United States, commercially available as Talwin® fromSanofi-Winthrop. Talwin® contains pentazocine hydrochloride equivalentto 50 mg base and naloxone hydrochloride equivalent to 0.5 mg base.Talwin® is indicated for the relief of moderate to severe pain. Theamount of naloxone present in this combination has no action when takenorally, and will not interfere with the pharmacologic action ofpentazocine. However, this amount of naloxone given by injection hasprofound antagonistic action to narcotic analgesics. Thus, the inclusionof naloxone is intended to curb a form of abuse of oral pentazocine,which occurs when the formulation is solubilized and injected.Therefore, this dosage has lower potential for parenteral abuse thanprevious oral pentazocine formulations.

Another example of attempts at preventing the potential harmful effectsof overdose includes compositions that have been coated with emetics ina quantity that if administered in moderation as intended no emesisoccurs, however, if excessive amounts are consumed emesis is inducedtherefore preventing overdose.

Scientists have reported the development and successful testing inlaboratory mice of a substance that shows promise for becoming the firstantidote for cocaine toxicity in humans. According to a report in ACS'Journal Molecular Pharmaceutics, the new so-called “passive vaccine”reversed the motor impairment, seizures and other dangerous symptoms ofa cocaine overdose, which claims thousands of lives each year amongusers of the illicit drug. Kim D. Janda and Jennifer B. Treweek explainthat their previous research established the validity of using vaccinesas treatments for drug addiction and contributed to the promotion of onecocaine-active vaccine (and three nicotine-active vaccines) to clinicalevaluation in humans. These so-called “active” vaccines elicitantibodies that bind circulating cocaine (and nicotine) molecules in theblood and prevent these drug molecules from reaching the brain. In doingso, vaccinated patients are “immune” to the drug's effects, and as aresult, they feel no pleasurable effects from the drug if they backslideduring recovery. The report describes the development of a cocainepassive vaccine, which consists of pre-formed human antibodies againstcocaine that are 10 times more potent in binding cocaine molecules. Thisimproved potency accelerates their ability to reverse cocaine toxicity,where time is of the essence. When administered by emergency medicalteams or in hospital emergency departments, these passive vaccines couldrepresent a life-saving therapeutic for overdose victims.

U.S. Pat. Nos. 6,277,384, 6,375,957, and 6,475,494 relate to oral dosageforms comprising a combination of an orally analgesically effectiveamount of an opioid agonist and an orally active opioid antagonist, theopioid antagonist being included in a ratio to the opioid agonist toprovide a combination product which is analgesically effective when thecombination is administered orally, but which is aversive in aphysically dependent subject. Preferably, the amount of opioidantagonist included in the combination product provides at least amildly negative, “aversive” experience in physically dependent addicts(e.g., precipitated abstinence syndrome).

There is still a need for formulations that prevent, inhibit, or delaydrug abuse such as by chewing and/or licking intact tablet(s), snorting,inhalation, smoking, and/or insufflation of pulverized or milledtablet(s) either accidentally or intentionally.

There is still a need for formulations that prevent, inhibit, or delayoverdose by ingesting too many unit dosage forms, either accidentally orintentionally.

SUMMARY

According to an aspect, there is provided a unit dose formulationcomprising at least one active substance, wherein release of said atleast one active substance is inhibited when the number of unit dosageforms ingested exceeds a predetermined number.

In an aspect, the unit dose formulation further comprises at least oneactuator and at least one regulator, whereby when the unit doseformulation is exposed to a fluid media having a process variable, and apredetermined threshold is established for the process variable, said atleast one regulator is capable of adjusting the variable to control therelease of said at least one active substance via said at least oneactuator.

In an aspect, said at least one regulator is present in an amountsufficient to raise the variable above the threshold, such thatdissolution of said at least one actuator and release of said at leastone active substance via the actuator is inhibited when the number ofunit dosage forms ingested exceeds the predetermined number.

In an aspect, said at least one regulator is present in an amountsufficient to decrease the variable below the threshold, such thatdissolution of said at least one actuator and release of said at leastone active substance via the actuator is inhibited when the number ofunit dosage forms ingested exceeds the predetermined number.

In an aspect, the fluid media is an acidic media.

In an aspect, the fluid media is a basic media.

In an aspect, the variable is pH.

In an aspect, the regulator and/or actuator is a physical/chemicalbarrier.

In an aspect, the regulator is a pH independent barrier and the actuatoris a pH dependent barrier.

In an aspect, said at least one regulator comprises at least onealkalinizing agent.

In an aspect, said at least one alkalinizing agent is selected from thegroup consisting of alkaline earth metal salts, alkali metal salts,aluminum salts, amino acids, amino acid derivatives, and combinationsthereof.

In an aspect, said at least one alkalinizing agent is selected from thegroup consisting of magnesium hydroxide, magnesium trisilicate, aluminumhydroxide, magnesium oxide, calcium carbonate, sodium bicarbonate,sodium citrate, sodium carbonate, sodium acetate, magnesium carbonate,L-arginine, meglumine, and combinations thereof.

In an aspect, said at least one alkalinizing agent is magnesiumhydroxide.

In an aspect, aid at least one regulator comprises at least oneacidifying agent.

In an aspect, said at least one regulator is selected from the groupconsisting of an inorganic acid, an organic acid, and combinationsthereof.

In an aspect, said at least one acidifying agent is selected from thegroup consisting of hydrochloric acid, sulfuric acid, nitric acid,lactic acid, phosphoric acid, citric acid, malic acid, fumaric acid,stearic acid, tartaric acid, boric acid, borax, benzoic acid, andcombinations thereof.

In an aspect, said at least one acidifying agent is fumaric acid and/orcitric acid.

In an aspect, said at least one actuator comprises at least one acidlabile substance.

In an aspect, said at least one acid labile substance is selected fromthe group consisting of sulfonamide-based polymers and copolymers, aminefunctional polymers such as polyvinyl pyridine polymers and copolymers,polysaccharides such as chitosan,poly(vinylpyrrolidone-co-dimethylmaleic anhydride) (PVD),dimethylaminoethyl methacrylate copolymers such as Eudragit E, EudragitE interpolyelectrolyte complex, Eudragit E polyamopholyte complex,Eudragit E interpolyelectrolyte complex with Eudragit L and/or EudragitS, derivatives thereof, and combinations thereof.

In an aspect, said at least one acid labile coat and/or substancecomprises Eudragit E.

In an aspect, said at least one actuator comprises at least one baselabile substance.

In an aspect, said at least one base labile substance is selected fromthe group consisting of pharmaceutically acceptable ethers, esters,ketones, epoxies, polyamides, polysiloxanes, enteric polymers, anioniccopolymers based on methacrylic acid and methyl methacrylate, andcombinations thereof.

In an aspect, said at least one base labile coat and/or substancecomprises at least one enteric polymer, such as Eudragit L or S.

In an aspect, wherein dissolution of said at least one actuator andrelease of said at least one active substance is reduced upondissolution of a threshold amount of said at least one regulator.

In an aspect, wherein dissolution of said at least one actuator andrelease of said at least one active substance decreases in the presenceof increasing concentrations of at least one regulator.

In an aspect, the rate of dissolution of said at least one actuator isinversely proportional to the number of unit dose formulations ingested.

In an aspect, wherein, when the number of unit dosage forms ingestedexceeds a predetermined number, said at least one regulator increasesthe pH to inhibit dissolution of said at least one actuator and inhibitrelease of said at least one active substance.

In an aspect, wherein, when the number of unit dosage forms ingestedexceeds a predetermined number, said at least one regulator decreasesthe pH to inhibit dissolution of said at least one actuator and inhibitrelease of said at least one active substance.

In an aspect, the predetermined number is less than 20.

In an aspect, the predetermined number is 1, 2, 3, 4, or 5.

In an aspect, the predetermined number is 1 or 2.

In an aspect, the unit dose formulation further comprises at least oneagent selected from the group consisting of an abuse deterrent coloringagent; a controlled release agent; a viscosity imparting agent; agelling agent; polyethylene oxide; crospovidone; Eudragit RL; EudragitRS, and combinations thereof.

In an aspect, the unit dose formulation further comprises at least oneabuse deterrent coloring agent.

In an aspect, wherein said at least one abuse deterrent coloring agentis brilliant blue; typically, Aluminum Lake Blue#1.

In an aspect, the unit dose formulation further comprises at least oneagent selected from the group consisting of a chewing discouragingagent, a licking discouraging agent, an insufflation discouraging agent,a snorting discouraging agent, an inhalation discouraging agent, andcombinations thereof.

In an aspect, the inhalation discouraging agent is selected from thegroup consisting of a coloring agent, a tussigenic agent, an irritant,and combinations thereof.

In an aspect, said at least one active substance is at least oneaddictive substance.

In an aspect, said at least one active substance is at least one opioidagonist and/or at least one narcotic analgesic.

In an aspect, said at least one active substance has an analgesicceiling effect.

In an aspect, the unit dose formulation in the form of a bead, tablet,capsule, granule, and/or pellet.

In an aspect, said at least one active substance is in an amount of fromabout 0.1 mg to about 1000 mg; said at least one actuator is in anamount of from about 0.5 mg to about 500 mg; and/or said at least oneregulator is in an amount of from about 0.5 mg to about 500 mg.

In an aspect, said at least one actuator is present in an amount of from0.5 mg/cm² to 200 mg/cm² or from 1 mg/cm² to 100 mg/cm² or from 2 mg/cm²to 150 mg/cm² or from about 4 mg/cm² to about 100 mg/cm² or from 8mg/cm² to 50 mg/cm².

In an aspect, said at least one actuator is present in an amount thatyields from about 1% to about 200% weight gain, from about 1% to about70% or from about 1% to about 50% weight gain.

In an aspect, said at least one regulator is present in an amount thatyields from about 1% to about 200% weight gain, from about 5% to about80%, from about 1% to about 70% weight gain, from about 1% to about 50%or from about 5% to about 50% weight gain.

In an aspect, wherein release of said at least one active substance is alag time, delayed release, no release or insignificant release of saidat least one active substance.

According to an aspect, there is provided a unit dose formulationcomprising:

a core comprising at least one active substance;

at least one acid labile coat surrounding the core; and

at least one alkalinizing coat surrounding said at least one acid labilecoat.

According to an aspect, there is provided a unit dose formulationcomprising:

a core comprising at least one active substance and at least one acidlabile substance; and

at least one alkalinizing coat surrounding the core.

According to an aspect, there is provided a unit dose formulationcomprising:

a core;

at least one acid labile coat surrounding the core, said at least oneacid labile coat comprising at least one acid labile substance and atleast one active substance; and

at least one alkalinizing coat surrounding said at least one acid labilecoat.

According to an aspect, there is provided a unit dose formulationcomprising:

a core;

at least one coat comprising at least one active substance;

at least one acid labile coat surrounding said at least one coat; and

at least one alkalinizing coat surrounding said at least one acid labilecoat.

According to an aspect, there is provided a unit dose formulationcomprising:

at least one active substance;

at least one acid labile coat surrounding said at least one activesubstance; and

at least one alkalinizing coat surrounding said at least one acid labilecoat.

According to an aspect, there is provided a unit dose formulationcomprising:

a mixture of at least one active substance and at least one acid labilesubstance; and

at least one alkalinizing coat surrounding the mixture.

In an aspect, the mixture is a homogeneous mixture.

In an aspect, said at least one alkalinizing coat is present in anamount sufficient to raise the pH of the stomach, such that dissolutionof said at least one acid labile coat and release of said at least oneactive substance is inhibited when the number of unit dosage formsingested exceeds a predetermined number.

In an aspect, said at least one alkalinizing coat is present in anamount sufficient to raise the pH of the stomach, such that dissolutionof said at least one acid labile substance and release of said at leastone active substance is inhibited when the number of unit dosage formsingested exceeds a predetermined number.

In an aspect, the predetermined number is less than 20.

In an aspect, the predetermined number is 1, 2, 3, 4, or 5.

In an aspect, the predetermined number is 1 or 2.

In an aspect, dissolution of said at least one acid labile coat andrelease of said at least one active substance is reduced upondissolution of a threshold amount of said at least one alkalinizingcoat.

In an aspect, dissolution of said at least one acid labile substance andrelease of said at least one active substance is reduced upondissolution of a threshold amount of said at least one alkalinizingcoat.

In an aspect, dissolution of said at least one acid labile coat andrelease of said at least one active substance is dependent upon theconcentration of at least one alkalinizing agent in said at least onealkalinizing coat.

In an aspect, dissolution of said at least one acid labile substance andrelease of said at least one active substance decreases in the presenceof increasing concentrations of at least one alkalinizing agent in saidat least one alkalinizing coat.

In an aspect, the rate of dissolution of said at least one acid labilecoat is inversely proportional to the number of unit dose formulationsingested.

In an aspect, the rate of dissolution of said at least one acid labilesubstance is inversely proportional to the number of unit doseformulations ingested.

In an aspect, wherein, when the number of unit dosage forms ingestedexceeds a predetermined number, said at least one alkalinizing coatincreases stomach pH to inhibit dissolution of said at least one acidlabile coat and inhibit release of said at least one active substance.

In an aspect, wherein, when the number of unit dosage forms ingestedexceeds a predetermined number, said at least one alkalinizing coatincreases stomach pH to inhibit dissolution of said at least one acidlabile substance and inhibit release of said at least one activesubstance.

In an aspect, each of said at least one alkalinizing coat comprises atleast one alkalinizing agent.

In an aspect, dissolution of said at least one acid labile coat and/orsubstance and release of said at least one active substance in aqueousmedium is dependent upon the concentration of said at least onealkalinizing agent in the aqueous medium.

In an aspect, said at least one alkalinizing agent is present in said atleast one alkalinizing coat in an amount such that:

when less than a predetermined number of unit dose formulations isingested, the gastric pH remains sufficiently acidic to dissolve said atleast one acid labile coat and/or substance and release said at leastone active substance; and

when the predetermined number or more of the unit dose formulations isingested, the gastric pH is alkalinized sufficiently to inhibitdissolution of said at least one acid labile coat and/or substance andrelease of said at least one active substance.

In an aspect, the predetermined number is 1, 2, 3, 4, or 5.

In an aspect, the predetermined number is 1 or 2.

In an aspect, said at least one alkalinizing agent is selected from thegroup consisting of alkaline earth metal salts, alkali metal salts,aluminum salts, amino acids, amino acid derivatives, and combinationsthereof.

In an aspect, said at least one alkalinizing agent is selected from thegroup consisting of magnesium hydroxide, magnesium trisilicate, aluminumhydroxide, magnesium oxide, calcium carbonate, sodium bicarbonate,sodium citrate, sodium carbonate, sodium acetate, magnesium carbonate,L-arginine, meglumine, and combinations thereof.

In an aspect, said at least one alkalinizing agent is magnesiumhydroxide.

In an aspect, each of said at least one acid labile coat comprises atleast one acid labile substance.

In an aspect, said at least one acid labile substance is selected fromthe group consisting of sulfonamide-based polymers and copolymers, aminefunctional polymers such as polyvinyl pyridine polymers and copolymers,polysaccharides such as chitosan,poly(vinylpyrrolidone-co-dimethylmaleic anhydride) (PVD),dimethylaminoethyl methacrylate copolymers such as Eudragit E, EudragitE interpolyelectrolyte complex, Eudragit E polyamopholyte complex,Eudragit E interpolyelectrolyte complex with Eudragit L and/or EudragitS, derivatives thereof, and combinations thereof.

In an aspect, said at least one acid labile coat and/or substancecomprises Eudragit E.

In an aspect, said at least one acid labile coat and/or acid labilesubstance dissolves in a solution with a pH of less than about 6, 5, 4,3, 2, or 1.

In an aspect, dissolution of said at least one acid labile coat and/oracid labile substance is inhibited in a solution with a pH of greaterthan about 3, 4, 5, or 6.

In an aspect, said at least one acid labile coat and/or said acid labilesubstance is soluble in stomach pH.

In an aspect, said at least one alkalinizing coat has at least onealkalinizing agent in an amount of at least about 1 mg per unit dosageformulation but such that when more unit dosage formulations thanprescribed are swallowed at once, the pH of the stomach changes to analkaline pH and release of said at least one active substance isinhibited.

In an aspect, the number of unit dosage formulations than thatprescribed is about 1 to about 100 and the stomach pH is less than about5, the pH of the stomach changes to alkaline pH.

In an aspect, the number of unit dosage formulations than thatprescribed is less than 20 and the stomach pH is less than about 4, thepH of the stomach changes to pH greater than about 4 and typically,greater than about 6.

In an aspect, said at least one active substance is homogenously mixedwithin the core; typically, the core comprises at least onedisintegrant, at least one Eudragit RL and Eudragit RS, at least onecoloring agent, and at least one polyethylene oxide.

In an aspect, the core comprises an outer active substance-releasingcoat beneath said at least one acid labile coat and/or alkalinizingcoat.

In an aspect, the core comprises a plurality of compressed granules.

In an aspect, the unit dosage formulation further comprises at least oneagent selected from the group consisting of an abuse deterrent coloringagent; a controlled release agent; a viscosity imparting agent; agelling agent; polyethylene oxide; crospovidone; Eudragit RL; EudragitRS, and combinations thereof.

In an aspect, the unit dose formulation further comprises at least oneabuse deterrent coloring agent.

In an aspect, wherein said at least one abuse deterrent coloring agentis brilliant blue; typically, Aluminum Lake Blue#1.

In an aspect, the unit dosage formulation further comprises at least oneagent selected from the group consisting of a chewing discouragingagent, a licking discouraging agent, an insufflation discouraging agent,a snorting discouraging agent, an inhalation discouraging agent, andcombinations thereof.

In an aspect, the inhalation discouraging agent is selected from thegroup consisting of a coloring agent, a tussigenic agent, an irritant,and combinations thereof.

In an aspect, the unit dose formulation further comprising said at leastone abuse deterrent coloring agent.

In an aspect, wherein said at least one abuse deterrent coloring agentis brilliant blue; typically, Aluminum Lake Blue#1.

In an aspect, said at least one active substance is at least oneaddictive substance.

In an aspect, said at least one active substance is at least one opioidagonist and/or at least one narcotic analgesic.

In an aspect, said at least one active substance has an analgesicceiling effect.

In an aspect, the unit dose formulation is in the form of a bead,tablet, capsule, granule, and/or pellet.

In an aspect, said at least one active substance is in an amount of fromabout 0.1 mg to about 1000 mg; said at least one acid labile coat is inan amount of from about 0.5 mg to about 500 mg; and/or said at least onealkalinizing coat is in an amount of from about 0.5 mg to about 500 mg.

In an aspect, said at least one acid labile coat is present in an amountof from 0.5 mg/cm² to 200 mg/cm² or from 1 mg/cm² to 100 mg/cm² or from2 mg/cm² to 150 mg/cm² or from about 4 mg/cm² to about 100 mg/cm² orfrom 8 mg/cm² to 50 mg/cm².

In an aspect, said at least one acid labile coat and/or acid labilesubstance is present in an amount that yields from about 1% to about200% weight gain, from about 1% to about 70% or from about 1% to about50% weight gain.

In an aspect, said at least one alkalinizing coat has a thickness offrom about 2 mg/cm² to about 100 mg/cm², or 15 mg/cm² to about 55mg/cm², or 10 mg/cm² to about 40 mg/cm², or 40 mg/cm² to about 80mg/cm², or 80 mg/cm² to about 100 mg/cm².

In an aspect, said at least one alkalinizing coat is present in anamount that yields from about 1% to about 200% weight gain, from about5% to about 80%, from about 1% to about 70% weight gain, from about 1%to about 50% or from about 5% to about 50% weight gain.

In an aspect, said at least one alkalinizing coat is partially,substantially or completely surrounding.

In an aspect, said at least one acid labile coat is substantially orcompletely surrounding.

In an aspect, the unit dose formulation is an immediate release orcontrolled release medication.

In an aspect, the alkalinizing coat contains at least one alkalinizingagent that is capable of undergoing the following neutralization withstomach acid:

MX₂+2HCl→MCl₂+2HX or MX₃+3HCl→MCl₃+3HX

where M is a metal ion and X is a basic ion.

According to an aspect, there is provided a unit dose formulationcomprising:

a core comprising at least one active substance;

at least one base labile coat surrounding the core;

at least one acidifying coat surrounding said at least one base labilecoat; and

at least one base labile coat surrounding said at least one acidifyingcoat.

According to an aspect, there is provided a unit dose formulationcomprising:

a core comprising at least one active substance and at least one baselabile substance;

at least one acidifying coat surrounding the core; and

at least one base labile coat surrounding said at least one acidifyingcoat.

According to an aspect, there is provided a unit dose formulationcomprising:

a core;

at least one base labile coat surrounding the core, said at least onebase labile coat comprising at least one base labile substance and atleast one active substance;

at least one acidifying coat surrounding said at least one base labilecoat; and

at least one base labile coat surrounding said at least one acidifyingcoat.

According to an aspect, there is provided a unit dose formulationcomprising:

a core;

at least one coat comprising at least one active substance;

at least one base labile coat surrounding said at least one coat;

at least one acidifying coat surrounding said at least one base labilecoat; and

at least one base labile coat surrounding said at least one acidifyingcoat.

According to an aspect, there is provided a unit dose formulationcomprising:

at least one active substance;

at least one base labile coat surrounding said at least one activesubstance;

at least one acidifying coat surrounding said at least one base labilecoat; and

at least one base labile coat surrounding said at least one acidifyingcoat.

According to an aspect, there is provided a unit dose formulationcomprising:

a mixture of at least one active substance and at least one base labilesubstance;

at least one acidifying coat surrounding the mixture; and

at least one base labile coat surrounding said at least one acidifyingcoat.

In an aspect, the mixture is a homogeneous mixture.

In an aspect, said at least one acidifying coat is present in an amountsufficient to lower the pH of the duodenum, such that dissolution ofsaid at least one base labile coat and release of said at least oneactive substance is inhibited when the number of unit dosage formsingested exceeds a predetermined number.

In an aspect, said at least one acidifying coat is present in an amountsufficient to lower the pH of the duodenum, such that dissolution ofsaid at least one base labile substance and release of said at least oneactive substance is inhibited when the number of unit dosage formsingested exceeds a predetermined number.

In an aspect, the predetermined number is less than 20.

In an aspect, the predetermined number is 1, 2, 3, 4, or 5.

In an aspect, the predetermined number is 1 or 2.

In an aspect, dissolution of said at least one base labile coat andrelease of said at least one active substance is reduced upondissolution of a threshold amount of said at least one acidifying coat.

In an aspect, dissolution of said at least one base labile substance andrelease of said at least one active substance is reduced upondissolution of a threshold amount of said at least one acidifying coat.

In an aspect, dissolution of said at least one base labile coat andrelease of said at least one active substance is dependent upon theconcentration of at least one acidifying agent in said at least oneacidifying coat.

In an aspect, dissolution of said at least one base labile substance andrelease of said at least one active substance decreases in the presenceof increasing concentrations of at least one acidifying agent in said atleast one acidifying coat.

In an aspect, the rate of dissolution of said at least one base labilecoat is inversely proportional to the number of unit dose formulationsingested.

In an aspect, the rate of dissolution of said at least one base labilesubstance is inversely proportional to the number of unit doseformulations ingested.

In an aspect, wherein, when the number of unit dosage forms ingestedexceeds a predetermined number, said at least one acidifying coatdecreases duodenum pH to inhibit dissolution of said at least one baselabile coat and inhibit release of said at least one active substance.

In an aspect, wherein, when the number of unit dosage forms ingestedexceeds a predetermined number, said at least one acidifying coatdecreases duodenum pH to inhibit dissolution of said at least one baselabile substance and inhibit release of said at least one activesubstance.

In an aspect, each of said at least one acidifying coat comprises atleast one acidifying agent.

In an aspect, dissolution of said at least one base labile coat and/orsubstance and release of said at least one active substance in aqueousmedium is dependent upon the concentration of said at least oneacidifying agent in the aqueous medium.

In an aspect, said at least one acidifying agent is present in said atleast one acidifying coat in an amount such that:

when less than a predetermined number of unit dose formulations isingested, the intestinal pH remains sufficiently basic to dissolve saidat least one base labile coat and/or substance and release said at leastone active substance; and

when the predetermined number or more of the unit dose formulations isingested, the intestinal pH is acidified sufficiently to inhibitdissolution of said at least one base labile coat and/or substance andrelease of said at least one active substance.

In an aspect, the predetermined number is 1, 2, 3, 4, or 5.

In an aspect, the predetermined number is 1 or 2.

In an aspect, said at least one acidifying agent is selected from thegroup consisting of an inorganic acid, an organic acid, and combinationsthereof.

In an aspect, said at least one acidifying agent is selected from thegroup consisting of hydrochloric acid, sulfuric acid, nitric acid,lactic acid, phosphoric acid, citric acid, malic acid, fumaric acid,stearic acid, tartaric acid, boric acid, borax, benzoic acid, andcombinations thereof.

In an aspect, said at least one acidifying agent is fumaric acid and/orcitric acid.

In an aspect, each of said at least one base labile coats comprise atleast one base labile substance.

In an aspect, said at least one base labile substance is selected fromthe group consisting of pharmaceutically acceptable ethers, esters,ketones, epoxies, polyamides, polysiloxanes, enteric polymers, anioniccopolymers based on methacrylic acid and methyl methacrylate, andcombinations thereof.

In an aspect, said at least one base labile coat and/or substancecomprises at least one enteric polymer, such as Eudragit L or S.

In an aspect, said at least one base labile coat and/or base labilesubstance dissolves in a solution with a pH of more than about 6, 7, 8,9, 10, or 11.

In an aspect, dissolution of said at least one base labile coat isinhibited in a solution with a pH of less than about 6, 5, 4, 3, or 2.

In an aspect, said at least one base labile coat and/or said base labilesubstance is soluble in duodenum pH.

In an aspect, said at least one acidifying coat has at least oneacidifying agent in an amount of at least about 1 mg per unit dosageformulation but such that when more unit dosage formulations thanprescribed are swallowed at once, the pH of the duodenum changes to anacidic pH and release of said at least one active substance isinhibited.

In an aspect, the number of unit dosage formulations than thatprescribed is about 1 to about 100 and the duodenum pH is greater thanabout 6, the pH of the stomach changes to acidic pH.

In an aspect, the number of unit dosage formulations than thatprescribed is less than 20 and the duodenum pH is greater than about 7,the pH of the duodenum changes to pH less than about 4 and typically,less than about 6.

In an aspect, said at least one active substance is homogenously mixedwithin the core, typically, the core comprises at least onedisintegrant, at least one Eudragit RL and Eudragit RS, at least onecoloring agent, and at least one polyethylene oxide.

In an aspect, the core comprises an outer active substance-releasinglayer beneath said at least one base and/or acid labile coat.

In an aspect, the core comprises a plurality of compressed granules.

In an aspect, the unit dose formulation further comprises at least oneagent selected from the group consisting of an abuse deterrent coloringagent; a controlled release agent; a viscosity imparting agent; agelling agent; polyethylene oxide;

crospovidone; Eudragit RL; Eudragit RS, and combinations thereof.

In an aspect, the unit dose formulation further comprises at least oneabuse deterrent coloring agent.

In an aspect, wherein said at least one abuse deterrent coloring agentis brilliant blue; typically, Aluminum Lake Blue#1.

In an aspect, the unit dose formulation further comprises at least oneagent selected from the group consisting of a chewing discouragingagent, a licking discouraging agent, an insufflation discouraging agent,a snorting discouraging agent, an inhalation discouraging agent, andcombinations thereof.

In an aspect, the inhalation discouraging agent is selected from thegroup consisting of a coloring agent, a tussigenic agent, an irritant,and combinations thereof.

In an aspect, the unit dose formulation further comprising said at leastone abuse deterrent coloring agent.

In an aspect, wherein said at least one abuse deterrent coloring agentis brilliant blue; typically, Aluminum Lake Blue#1.

In an aspect, said at least one active substance is at least oneaddictive substance.

In an aspect, said at least one active substance is at least one opioidagonist and/or at least one narcotic analgesic.

In an aspect, said at least one active substance has an analgesicceiling effect.

In an aspect, the unit dose formulation is in the form of a bead,capsule, tablet, granule, and/or pellet.

In an aspect, said at least one active substance is in an amount of fromabout 0.1 mg to about 1000 mg; said at least one base labile coat is inan amount of from about 0.5 mg to about 500 mg; and/or said at least oneacidifying coat is in an amount of from about 0.5 mg to about 500 mg.

In an aspect, said at least one base labile coat is present in an amountof from 0.5 mg/cm² to 200 mg/cm² or from 1 mg/cm² to 100 mg/cm² or from2 mg/cm² to 150 mg/cm² or from about 4 mg/cm² to about 100 mg/cm² orfrom about 0.5 to about 50 mg/cm² or from about 8 to about 50 mg/cm² orfrom about 0.5 to about 8 mg/cm².

In an aspect, said at least one base labile coat and/or base labilesubstance is present in an amount that yields from about 1% to about200% weight gain, from about 1% to about 70% or from about 1% to about50% weight gain.

In an aspect, said at least one acidifying coat has a thickness of fromabout 2 mg/cm² to about 100 mg/cm², or 15 mg/cm² to about 55 mg/cm², or10 mg/cm² to about 40 mg/cm², or 40 mg/cm² to about 80 mg/cm², or 80mg/cm² to about 100 mg/cm².

In an aspect, said at least one acidifying coat is present in an amountthat yields from about 1% to about 200% weight gain, from about 5% toabout 80%, from about 1% to about 70% weight gain, from about 1% toabout 50% or from about 5% to about 50% weight gain.

In an aspect, said at least one acidifying coat is partially,substantially or completely surrounding.

In an aspect, said at least one base labile coat is substantially orcompletely surrounding.

In an aspect, the unit dose formulation is an immediate release orcontrolled release medication.

In an aspect, said at least one active comprises a known/commercial drugformulation.

In an aspect, said at least one active comprises multivitamins, Tylenol,Aspirin, Oxycodone, Hydrocodone, Oxymorphone, Hydromorphone, Morphine,Codeine, or combinations thereof.

In an aspect, an insignificant amount of said at least one activesubstance or less is released when the number of unit dosage formsingested exceeds a predetermined number.

In an aspect, wherein when more than the recommended dose is ingested atonce, an insignificant amount or less of said at least one activesubstance is released.

In an aspect, wherein when more than the recommended dose is ingested atonce, there is a lag time before a significant amount of said at leastone active substance is released.

In an aspect, wherein when between 2 to 10 unit dose forms, or between11 to 20 unit dose forms, or between 21 to 30 unit dose forms, orbetween 31 to 40 unit dose forms, or between 41 to 50 unit dose forms,or between 51 to 100 unit dose forms are swallowed intact, theformulation delays, reduces or prevents the instantaneous release of allor significant amounts of said at least one active substance.

In an aspect, wherein when greater than 100 unit dose forms areswallowed intact, the formulation delays, reduces or prevents theinstantaneous release of all or significant amounts of said at least oneactive substance.

In an aspect, the pharmacokinetic profile on single dosageadministration during fasting and/or feed conditions shows a high rateof input of said at least one active substance in the first hour whichis at least 5 times the rate of input of said at least one activesubstance at subsequent hourly intervals.

In an aspect, said formulation is about 40 mg oxycodone hydrochlorideform wherein the pharmacokinetic profile on single dose administrationshows a mean plasma concentration per unit of time of between about 15ng/ml and about 35 ng/ml between about the first hour and about thesixth hour.

In an aspect, a capsule comprising the unit dose formulation asdescribed herein.

In an aspect, wherein said at least one active substance is an over thecounter (OTC) medication.

According to an aspect, there is provided a method of inhibiting orpreventing overdose, the method comprising administering the unit doseformulation or the capsule described herein.

According to an aspect, there is provided a method of treating orpreventing euphoria and/or addiction, the method comprisingadministering the unit dose formulation or the capsule described herein.

According to an aspect, there is provided a method of discouragingabuse, the method comprising administering the unit dose formulation orthe capsule described herein.

According to an aspect, there is provided a method of delaying euphoriaand/or overdose, the method comprising administering the unit doseformulation or the capsule described herein.

According to an aspect, there is provided a method of preventing suicideor accidental death from overdose or euphoria, the method comprisingadministering the unit dose formulation or the capsule described herein.

According to an aspect, there is provided a method of managingcondition(s), disorder(s) and/or disease(s), the method comprisingadministering the unit dose formulation or the capsule described herein.

According to an aspect, there is provided a method of managing at leastone of pain, insomnia, depression, schizophrenia, attention deficithyperactivity disorder, epilepsy, cardiovascular diseases, diabetes, andneuropathic pain, the method comprising administering the unit doseformulation or the capsule described herein.

In an aspect, said at least one active substance is an over the counter(OTC) medication.

According to an aspect, there is provided a use of the unit doseformulation or the capsule described herein to inhibit or preventoverdose.

According to an aspect, there is provided a use of the unit doseformulation or the capsule described herein to treat or preventaddiction.

According to an aspect, there is provided a use of the unit doseformulation or the capsule described herein to discourage abuse.

According to an aspect, there is provided a use of the unit doseformulation or the capsule described herein to delay overdose oreuphoria.

According to an aspect, there is provided a use of the unit doseformulation or the capsule described herein to prevent suicide oraccidental death from overdose or euphoria.

According to an aspect, there is provided a use of the unit doseformulation or the capsule described herein for managing condition(s),disorder(s) and/or disease(s).

According to an aspect, there is provided a use of the unit doseformulation or the capsule described herein for managing at least one ofpain, insomnia, depression, schizophrenia, attention deficithyperactivity disorder, epilepsy, cardiovascular diseases, diabetes, andneuropathic pain.

In an aspect, said at least one active substance is an over the counter(OTC) medication.

Other features and advantages of the present invention will becomeapparent from the following detailed description. It should beunderstood, however, that the detailed description and the specificexamples while indicating embodiments of the invention are given by wayof illustration only, since various changes and modifications within thespirit and scope of the invention will become apparent to those skilledin the art from the detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

Embodiments of the present invention will now be described, by way ofexample only, with reference to the attached Figures.

FIG. 1 shows the effects of magnesium hydroxide on the pH of an acidicsolution over a 60 minute timecourse in amounts ranging from 60-120mg/320 ml acidic solution and from 60-240 mg/500 ml acidic solution.

FIG. 2 shows the effects of magnesium oxide and calcium carbonate on thepH of an acidic solution over a 60 minute timecourse in various amounts.

FIG. 3 shows the effects of sodium bicarbonate on the pH of an acidicsolution over a 60 minute timecourse in amounts of 20 mg/320 ml acidicsolution and 40 mg/320 ml acidic solution.

FIG. 4 shows the effects of magnesium oxide on the pH of an acidicsolution over a 60 minute timecourse in amounts of 80-120 mg/200 mlacidic solution, in powder form. Additionally shown is a 60 minutetimecourse for an amount of 80 mg magnesium oxide in granular form in200 ml acidic solution.

FIG. 5 shows the effects of magnesium hydroxide on the pH of an acidicsolution over a 60 minute timecourse in amounts of 60-100 mg/200 mlacidic solution.

FIG. 6 shows the effects of calcium carbonate on the pH of an acidicsolution over a 60 minute timecourse in amounts of 120-140 mg/200 mlacidic solution.

FIG. 7 shows the effects of magnesium hydroxide and calcium carbonate incombination on the pH of an acidic solution over a 60 minute timecoursein amounts of 50-71.25 mg magnesium hydroxide per 200 ml acidic solutionand from 50.95-150.35 mg calcium carbonate per 200 ml acidic solution.

FIG. 8 shows the effects of 930 mg sodium citrate, 200 mg sodiumacetate, 100 mg L-arginine-HCl, 100 mg magnesium carbonate, and 120 mgmeglumine on the pH of an acidic solution over a 60 minute timecourse in200 ml acidic solution.

FIG. 9 shows the effects of sodium carbonate on the pH of an acidicsolution over a 60 minute timecourse in amounts of 11.13-81.68 mg/200 mlacidic solution.

FIG. 10 shows the effects of sodium bicarbonate on the pH of an acidicsolution over a 40 minute timecourse in amounts of 50 and 100 mg/200 mlacidic solution (overlap).

FIG. 11 shows the effect of 10 mg sodium lauryl sulfate on the pH of anacidic solution over a 30 minute timecourse in 200 ml acidic solution.

FIG. 12 shows the effect of 80 mg magnesium carbonate on the pH of anacidic solution over a 30 minute timecourse in 200 ml acidic solution.

FIGS. 13A and 13B show that the dissolution of the tablets of Example 2in an acidic solution is inversely proportional to the number of tabletsadded to the solution.

FIG. 13A is a graph showing the rate and extent of dissolution of 1-6tablets in the acidic solution. FIG. 13B is a graph showing the rate andextent of dissolution of 10, 20, 40, 60, 80, and 100 tablets in theacidic solution. FIGS. 13C through 13H show the dissolution of thetablets of Example 2 in an acidic solution. FIG. 13C is an image of onetablet in the acidic solution. FIG. 13D is 10. an image of two tabletsin the acidic solution. FIG. 13E is an image of three tablets in theacidic solution. FIG. 13F is an image of four tablets in the acidicsolution. FIG. 13G is an image of five tablets in the acidic solution.FIG. 13H is an image of six tablets in the acidic solution.

FIGS. 14A and 14B show that the dissolution of the tablets of Example 4in an acidic solution is inversely proportional to the number of tabletsadded to the solution.

FIGS. 14C through 14H show the dissolution of the tablets of Example 4in an acidic solution. FIG. 14C is an image of one tablet in the acidicsolution. FIG. 14D is an image of two tablets in the acidic solution.FIG. 14E is an image of three tablets in the acidic solution. FIG. 14Fis an image of four tablets in the acidic solution. FIG. 14G is an imageof five tablets in the acidic solution. FIG. 14H is an image of sixtablets in the acidic solution.

FIGS. 15A and 15B show that the dissolution of the tablets of Example 6in an acidic solution is inversely proportional to the number of tabletsadded to the solution.

FIG. 15A is a graph showing the rate and extent of dissolution of 1-6tablets in the acidic solution. FIG. 15B is a graph showing the rate andextent of dissolution of 10, 20, 40, 60, 80, and 100 tablets in theacidic solution. FIGS. 15C through 15K show the dissolution of thetablets of Example 6 in an acidic solution. FIG. 15C is an image of onetablet in the acidic solution. FIG. 15D is an image of two tablets inthe acidic solution. FIG. 15E is an image of three tablets in the acidicsolution. FIG. 15F is an image of four tablets in the acidic solution.FIG. 15G is an image of five tablets in the acidic solution. FIG. 15H isan image of six 35 tablets in the acidic solution. FIG. 15I is an imageof 10 tablets in the acidic solution, FIG. 15J is an image of 20 tabletsin the acidic solution. FIG. 15K is an image of 50 tablets in the acidicsolution.

FIG. 15L. is a graph showing the rate and extent of dissolution of 10,20, 30, and 40 tablets in the acidic solution.

FIG. 15M is a graph showing the rate and extent of dissolution of 10,20, 30, 40, 50, and 100 tablets in the acidic solution.

FIGS. 16A and 16B show a comparison of drug release between tablets ofExamples 2, 4, and 6 were added to an acidic solution. FIG. 16A is agraph showing the comparison of drug release when 100 tablets from eachexample was added to the acidic solution. FIG. 16B is of images of 1-6tablets from each example after a time period of incubation in theacidic solution.

FIG. 17 shows dissolution of various quantities of intact Rexista OxyC80 mg Tablets (ODRA type1) One tablet of Rexista OxyC 80 mg (ODRAtype1): Media 0.01N HCl, 37° C., Paddle Speed 100 RPM.

FIG. 18 shows a comparison of different physical states of intact,broken and ground (using mortar and pestle) of Rexista Oxycodone ERtablets from Example 29 vs. Commercially available Oxycodone HCl (ER)tablets.

FIG. 19 shows Rexista Oxycodone ER tablets from Example 29 broken,showing cross section of a blue colored core containing abuse deterrentcoloring agent FIG. 20 shows particles of Rexista Oxycodone ER tabletsfrom Example 29 formed after grinding an intact tablet (using mortar andpestle) showing the blue colored core containing an abuse deterrentcoloring agent.

FIG. 21 shows formation of a disagreeable blue colored viscous stickygel when particles from Rexista Oxycodone ER tablets from Example 29 areground (using mortar and pestle) and are placed in contact with 5 ml ofwater. Blue color is due to abuse deterrent coloring agent.

FIG. 22 shows formation of a disagreeable blue colored viscous stickygel which is difficult to syringe when particles from Rexista OxycodoneER tablets from Example 29 are ground (using mortar and pestle) and areplaced in contact with 10 ml of water. Blue color is due to abusedeterrent coloring agent.

FIG. 23 shows that when particles from Rexista Oxycodone ER tablets fromExample 29 are ground (using mortar and pestle) and are placed incontact with water for the purpose of abusing it via intravenousinjection; it is difficult to fill it into a syringe due to theformation of a disagreeable blue colored viscous sticky gel.

FIG. 24 shows Rexista Oxycodone ER 80 mg tablets from Example 29 that isintact and therefore, does not stain the hands with the disagreeableabuse deterrent coloring agent as it is incorporated in the tablet core.

FIG. 25 shows that crushing and handling Rexista Oxycodone ER 80 mgtablets from Example 29 for the purpose of abuse, releases and leavesbehind the disagreeable abuse deterrent coloring agent that wasincorporated in the tablet core.

FIG. 26 shows that chewing and licking of Rexista Oxycodone ER 80 mgtablets from Example 29 for the purpose of abuse, releases and leavesbehind the disagreeable abuse deterrent coloring agent incorporated inthe tablet core, resulting in a disgusting blue coloration of thetongue, lips, teeth and mouth thus, stigmatizing the individual.

FIG. 27 shows mean plasma oxycodone concentration vs. time, Rexista 40mg tablets vs. Commercially available Oxycodone HCl (ER) 40 mg tablets(Reference) under fasting condition.

FIG. 28 shows mean plasma oxycodone concentration vs. time, Rexista 40mg tablets vs. Commercially available Oxycodone HCl (ER) 40 mg tablets(Reference) under fed conditions.

FIG. 29 shows oral multiple dose simulation pharmacokinetic modelling ofmean plasma oxycodone concentration vs. time, Rexista 40 mg tablets vs.Commercially available Oxycodone HCl (ER) 40 mg tablets.

FIG. 30 shows result of vaporization studies of Rexista Oxycodone ER 80mg tablets from Example 29 vs Commercially available Oxycodone HCl (ER).

FIG. 31 shows effect of subjecting pulverized particles of Rexista to anopen flame.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS Definitions

The terms “overdose” or “overdosing” describe the ingestion orapplication of a drug or other substance in quantities greater than arerecommended, prescribed, or generally practiced. An overdose is widelyconsidered harmful and dangerous and may result in toxicity or death. Anoverdose may be intentional or accidental. This term also thereforeencompasses a method of suicide or attempted suicide that involvestaking medication in higher than recommended doses or in combinationsthat will interact to cause harmful effects or increase the potency ofanother drug. Accidental overdose may occur by failure to read orunderstand product labels or as a result of over-prescription, failureto recognize a drug's active ingredient, or by unwitting ingestion bychildren. A common unintentional overdose in children involves ingestionof multi-vitamins containing iron. Unintentional misuse leading tooverdose can also include using prescribed or un-prescribed drugs inexcessive quantities in an attempt to produce euphoria. Usage of illicitdrugs of unexpected purity, in large quantities, or after a period ofdrug abstinence can also induce overdose. Cocaine users who injectintravenously can easily overdose accidentally, as the margin between apleasurable drug sensation and an overdose is small.

The terms “formulation” and “composition” may be used interchangeably. A“unit dose formulation” or “unit dose form” is a formulation orcomposition in a single dose size. Examples include pills, tablets,caplets, capsules, etc.

The term “active ingredient,” “active agent,” or “active substance”means any compound which has biological, chemical, or physiologicalutility including, without limitation, active pharmaceutical ingredient,drug, naturally occurring compound, nucleic acid compound, peptidecompound, biologics, nutraceutical, agricultural or nutritionalingredient or synthetic drug, including addictive substances such asopioid agonists or narcotic analgesics, hypnotics, tranquilizers,stimulants and antidepressants.

The terms “primary” and “secondary” used in conjunction with “activeingredient” were used to assist simply for antecedent purposes and arenot meant to imply the level of importance of the active ingredient.

The term “insufflation” means the practice of blowing or breathingmedicated material or powder into the lungs or inhaling or snorting asubstance. “Insufflation discouraging agents” include, for example,irritants and tussigenic agents. The term “irritant” includes a compoundused to impart an irritating or burning sensation. The term “tussigenic”includes a compound used to cause coughing.

The term “addictive substance” means any compound upon which a user maydevelop a psychic or physical dependence, including, without limitation,any active ingredient or active substance as defined herein that mayhave this property.

Many interchangeable terms are commonly used to describe the psychic orphysical dependence of people upon compounds. The term addiction is mostcommonly used when talking about the strong analgesics or opioid agonistor abuse-able substances. The strong analgesics or opioid agonist orabuse-able substances, in contrast to the weaker agents such as aspirin,acetaminophen, and the like, are employed in the relief of more severepain. They usually produce a euphoric effect when crushed and swallowed,snorted, or when modified for “shooting” parenterally. When taken asprescribed there is usually no significant euphoria.

Addictive substances also include drugs most commonly employed forillicit purposes (to bring about a “high”, euphoria, excitement, stupor,sleep deprivation etc.) such as the barbiturates, lysergic aciddiethylamide (LSD), mescaline, marijuana (tetrahydrocannabinol), heroin,and the like, the central nervous system stimulants (the amphetaminesand the like) sedative, hypnotics and some of the major and minortranquilizers (the promazines, meprobamate, the diazepines, and thelike).

Examples of some of the opioid agonists or narcotic analgesicscontemplated for use in this invention include alfentanil, allylprodine,alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine,butorphanol, clonitazene, codeine, desomorphine, dextromoramide,dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine,dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate,dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene,ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanylhydrocodone, hydromorphone, hydroxypethidine, isomethadone,ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine,meptazinol, metazocine, methadone, metopon, morphine, myrophine,narceine, nicomorphine, norlevorphanol, normethadone, nalorphine,nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone,papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine,phenoperidine, piminodine, piritramide, propheptazine, promedol,properidine, propoxyphene, sufentanil, tramadol, tilidine, alphaprodine,dextroporpoxyphene, propiram, profadol, phenampromide, thiambutene,pholcodeine,3-trans-dimethylamino-4-phenyl-4-trans-carbethoxy-delta-cyclohexene,3-dimethylamino-O-(4-methoxyphenylcarbamoyl)-propiophenone oxime,(−)β-2′-hydroxy-2,9-dimethyl-5-phenyl-6,7-benzomorphan,(−)2′-hydroxy-2-(3-methyl-2-butenyl)-9-methyl-5-phenyl-6,7-benzomorphan,pirinitramide, (−)α-5,9-diethyl-2′-hydroxy-2-methyl-6,7-benzomorphan,ethyl-1-(2-dimethylaminoethyl)-4,5,6,7-tetrahydro-3-methyl-4-oxo-6-phenylindole-2-carboxylate,1-benzoylmethyl-2,3-dimethyl-3-(m-hydroxyphenyl)-piperidine,N-allyl-7α-(1-(R)-hydroxy-1-methylbutyl)-6,14-endo-ethanotetrahydronororipavine, (−)2′-hydroxy-2-methyl-6,7-benzomorphan, noracylmethadol,phenoperidine, α-dl-methadol, β-dl-methadol, α-1-methadol,β-dl-acetylmethadol, α-1-acetylmethadol and β-1-acetylmethadol andpharmaceutically acceptable salts thereof, stereoisomers thereof, ethersthereof, esters thereof, and mixtures thereof and their prodrugs in eachcase.

Furthermore, in certain embodiments, the formulations described hereinmay be particular suitable for inhibiting, preventing, or delayingoverdose of a pharmaceutical active ingredient selected from the groupconsisting of opiates, opioids, tranquilizers, typicallybenzodiazepines, barbiturates, stimulants and other narcotics and theirprodrugs in each case. The formulations may be particularly suitable forpreventing abuse of an opiate, opioid, tranquilizer or another narcoticselected from the group consisting ofN-{1-[2-(4-ethyl-5-oxo-2-tetrazolin-1-yl)ethyl]-4-methoxymethyl-4-piperid-yl}propionanilide(alfentanil), 5,5-diallylbarbituric acid (allobarbital), allylprodine,alphaprodine,8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]-benzodiazepine(alprazolam), 2-diethylaminopropiophenone (amfepramone),(+)-α-methyl-phenethylamine (amphetamine),2-α-methylphenethylamino)-2-phenylacetonitrile (amphetaminil),5-ethyl-5-isopentylbarbituric acid (amobarbital), anileridine,apocodeine, 5,5-diethylbarbituric acid (barbital), benzylmorphine,bezitramide, 7-bromo-5-(2-pyridyl)-1H-1,4-benzodiazepine-2(3H)-one(bromazepam),2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo-[4,3-a][1,4]diazepine(brotizolam),17-cyclopropylmethyl-4,5α-epoxy-7α[(S)-1-hydroxy-1,2,2-trimethyl-propyl]-6-methoxy-6,14-endo-ethanomorphinane-3-ol(buprenorphine), 5-butyl-5-ethylbarbituric acid (butobarbital),butorphanol,(7-chloro-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepine-3-yl)-dimethylcarbamate(camazepam), (1S,2S)-2-amino-1-phenyl-1-propanol(cathine/D-norpseudoephedrine),7-chloro-N-methyl-5-phenyl-3H-1,4-benzodiazepine-2-ylamine-4-oxide(chlorodiazepoxide),7-chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione(clobazam), 5-(2-chlorophenyl)-7-nitro-1H-1,4-benzodiazepine-2(3H)-one(clonazepam), clonitazene,7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylicacid (clorazepate),5-(2-chlorophenyl)-7-ethyl-1-methyl-1H-thieno[2,3-e][1,4]diazepine-2(3H)-one(clotiazepam),10-chloro-11b-(2-chlorophenyl)-2,3,7,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepine-6(5H)-one(cloxazolam),(−)-methyl-[3β-benzoyloxy-2-β(1α(H,5-αH)-tropancarboxylate] (cocaine),4,5-α-epoxy-3-methoxy-17-methyl-7-morphinene-6-α-ol (codeine),5-(1-cyclohexenyl)-5-ethylbarbituric acid (cyclobarbital), cyclorphan,cyprenorphine,7-chloro-5-(2-chlorophenyl)-1H-1,4-benzodiazepine-2(3H)-one(delorazepam), desomorphine, dextromoramide,(+)-(1-benzyl-3-dimethylamino-2-methyl-1-phenylpropyl)propionate(dextropropoxyphen), dezocine, diampromide, diamorphone,7-chloro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-2(3H)-one (diazepam),4,5-α-epoxy-3-methoxy-17-methyl-6-α-morphinanol (dihydrocodeine),4,5-α-epoxy-17-methyl-3,6-α-morphinandiol (dihydromorphine),dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate,dipipanone,(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-1-ol(dronabinol), eptazocine,8-chloro-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine(estazolam), ethoheptazine, ethylmethylthiambutene, ethyl[7-chloro-5-(2-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-3-carboxylate](ethylloflazepate), 4,5-α-epoxy-3-ethoxy-17-methyl-7-morphinene-6-α-ol(ethylmorphine), etonitazene,4,5-α-epoxy-7-α-(1-hydroxy-1-methylbutyl)-6-methoxy-17-methyl-6,14-endo-etheno-morphinan-3-ol(etorphine), N-ethyl-3-phenyl-8,9,10-trinorbornan-2-ylamine(fencamfamine), 7-[2-(1-methyl-phenethylamino)ethyl]-theophylline)(fenethylline), 3-(α-methylphenethylamino)propionitrile (fenproporex),N-(1-phenethyl-4-piperidyl)propionanilide (fentanyl),7-chloro-5-(2-fluorophenyl)-1-methyl-1H-1,4-benzodiazepine-2(3H)-one(fludiazepam),5-(2-fluorophenyl)-1-methyl-7-nitro-1H-1,4-benzodiazepine-2(3H)-one(flunitrazepam),7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1H-1,4-benzodiazepine-2(3H)-one(flurazepam),7-chloro-5-phenyl-1-(2,2,2-trifluoroethyl)-1H-1,4-benzodiazepine-2(3H)-one(halazepam),10-bromo-11b-(2-fluorophenyl)-2,3,7,11b-tetrahydro[1,3]oxazolyl[3,2-d][1,-4]benzodiazepine-6(5H)-one(haloxazolam), heroin, 4,5-α-epoxy-3-methoxy-17-methyl-6-morphinanone(hydrocodone), 4,5-α-epoxy-3-hydroxy-17-methyl-6-morphinanone(hydromorphone), hydroxypethidine, isomethadone, hydroxymethylmorphinane,11-chloro-8,12b-dihydro-2,8-dimethyl-12b-phenyl-4H-[1,3]oxazino[3,2-d][1,4]benzodiazepine-4,7(6H)-dione(ketazolam), 1-[4-(3-hydroxyphenyl)-1-methyl-4-piperidyl]-1-propanone(ketobemidone), (3S,6S)-6-dimethylamino-4,4-diphenylheptan-3-yl acetate(levacetylmethadol (LAAM)),(−)-6-dimethyl-amino-4,4-diphenol-3-heptanone (levomethadone),(−)-17-methyl-3-morphinanol (levorphanol), levophenacylmorphane,lofentanil,6-(2-chlorophenyl)-2-(4-methyl-1-piperazinylmethylene)-8-nitro-2H-imidazo-[1,2-a][1,4]-benzodiazepine-1(4H)-one(loprazolam),7-chloro-5-(2-chlorophenyl)-3-hydroxy-1H-1,4-benzodiazepine-2(3H)-one(lorazepam),7-chloro-5-(2-chlorophenyl)-3-hydroxy-1-methyl-1H-1,4-benzodiazepine-2(3H)-one(lormetazepam),5-(4-chlorophenyl)-2,5-dihydro-3H-imidazo[2,1-a]isoindol-5-ol(mazindol), 7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine(medazepam), N-(3-chloropropyl)-α-methylphenethylamine (mefenorex),meperidine, 2-methyl-2-propyltrimethylene dicarbamate (meprobamate),meptazinol, metazocine, methylmorphine, N,α-dimethylphenethylamine(methamphetamine), (±)-6-dimethylamino-4,4-diphenyl-3-heptanone(methadone), 2-methyl-3-o-tolyl-4(3H)-quinazolinone (methaqualone),methyl [2-phenyl-2-(2-piperidyl)acetate](methylphenidate),5-ethyl-1-methyl-5-phenylbarbituric acid (methylphenobarbital),3,3-diethyl-5-methyl-2,4-piperidinedione (methyprylon), metopon,8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine(midazolam), 2-(benzhydrylsulfinyl)-acetamide (modafinil),4,5-α-epoxy-17-methyl-7-morphinen-3,6-α-diol (morphine), myrophine,(±)-trans-3-(1,1-dimethylheptyl)-7,8,10,11-α-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyrane-9(6-αH)-one (nabilone), nalbuphine, nalorphine, narceine, nicomorphine,1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepine-2(3H)-one (nimetazepam),7-nitro-5-phenyl-1H-1,4-benzodiazepine-2(3H)-one (nitrazepam),7-chloro-5-phenyl-1H-1,4-benzodiazepine-2(3H)-one (nordazepam),norlevorphanol, 6-dimethylamino-4,4-diphenyl-3-hexanone (normethadone),normorphine, norpipanone, the exudation of plants belonging to thespecies Papaver somniferum (opium),7-chloro-3-hydroxy-5-phenyl-1H-1,4-benzodiazepine-2(3H)-one (oxazepam),(cis-trans)-10-chloro-2,3,7,11b-tetrahydro-2-methyl-11b-phenyloxazolo[3,2-d][1,4]benzodiazepine-6-(5H)-one(oxazolam), 4,5-α-epoxy-14-hydroxy-3-methoxy-17-methyl-6-morphinanone(oxycodone), oxymorphone, plants and parts of plants belonging to thespecies Papaver somniferum (including the subspecies setigerum),papaveretum, 2-imino-5-phenyl-4-oxazolidinone (pernoline),1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methano-3-benzazocin-8-ol(pentazocine), 5-ethyl-5-(1-methylbutyl)-barbituric acid(pentobarbital), ethyl-(1-methyl-4-phenyl-4-piperidine carboxylate)(pethidine), phenadoxone, phenomorphan, phenazocine, phenoperidine,piminodine, pholcodine, 3-methyl-2-phenylmorpholine (phenmetrazine),5-ethyl-5-phenylbarbituric acid (phenobarbital), α,α-dimethylphenethylamine (phentermine),7-chloro-5-phenyl-1-(2-propynyl)-1H-1,4-benzodiazepine-2(3H)-one(pinazepam), α-(2-piperidyl)benzhydryl alcohol (pipradrol),1′-(3-cyano-3,3-diphenylpropyl)[1,4′-bipiperidine]-4′-carboxamide(piritramide),7-chloro-1-(cyclopropylmethyl)-5-phenyl-1H-1,4-benzodiazepine-2(3H)-one(prazepam), profadol, proheptazine, promedol, properidine, propoxyphene,N-(1-methyl-2-piperidinoethyl)-N-(2-pyridyl)propionamide, methyl{3-[4-methoxycarbonyl-4-(N-phenylpropanamido)piperidino]propanoate}(remifentanil), 5-sec-butyl-5-ethylbarbituric acid (secbutabarbital),5-allyl-5-(1-methylbutyl)-barbituric acid (secobarbital),N-{4-methoxymethyl-1-[2-(2-thienyl)ethyl]-4-piperidyl}-propionanilide(sufentanil),7-chloro-2-hydroxy-methyl-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one(temazepam),7-chloro-5-(1-cyclohexenyl)-1-methyl-1H-1,4-benzodiazepine-2(3H)-one(tetrazepam),ethyl(2-dimethylamino-1-phenyl-3-cyclohexene-1-carboxylate) (tilidine(cis and trans)), tramadol,8-chloro-6-(2-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzod-iazepine(triazolam), 5-(1-methylbutyl)-5-vinylbarbituric acid (vinylbital),(1R*,2R*)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,(1R,2R,4S)-2-(dimethylamino)methyl-4-(p-fluoro-benzyloxy)-1-(m-methoxyphenyl)cyclohexanol,(1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)phenol,(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol,(2R,3R)-1-dimethylamino-3(3-methoxyphenyl)-2-methyl-pentan-3-ol,(1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol,3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl2-(4-isobutoxy-phenyl)-propionate,3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl2-(6-methoxy-naphthalen-2-yl)-propionate,3-(2-dimethylamino-methyl-cyclohex-1-enyl)-phenyl2-(4-isobutyl-phenyl)-propionate,3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl2-(6-methoxy-naphthalen-2-yl)-propionate,(RR—SS)-2-acetoxy-4-trifluoromethyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR—SS)-2-hydroxy-4-trifluoromethyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR—SS)-4-chloro-2-hydroxy-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR—SS)-2-hydroxy-4-methyl-benzoic acid3-(2-dimethylamino-methyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR—SS)-2-hydroxy-4-methoxy-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR—SS)-2-hydroxy-5-nitro-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR—SS)-2′,4′-difluoro-3-hydroxy-biphenyl-4-carboxylic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester and forcorresponding stereoisomeric compounds, the corresponding derivativesthereof in each case, in particular esters or ethers, and thephysiologically acceptable compounds thereof in each case, in particularthe salts and solvates thereof, and their prodrugs in each case. Thecompounds (1R*,2R*)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,(1R,2R,4S)-2-(dimethylamino)methyl-4-(p-fluorobenzyloxy)-1-(m-methoxyphenyl)cyclohexanolor the stereoisomeric compounds thereof or the physiologicallyacceptable compounds thereof, in particular the hydrochlorides thereof,the derivatives thereof, such as esters or ethers, and processes for theproduction thereof are known, for example, from EP-A-693475 orEP-A-780369.

The formulations herein may also contain other active ingredients. Theseinclude, amongst others and for example, opioid antagonists (such asnaloxone), aspirin, phenacetin, caffeine, acetaminophen, antihistamines,homatropine methylbromide, phenyltoloxamine citrate, barbiturates, orthe like, or multiple combinations thereof.

Formulations herein may also comprise narcotic analgesics in combinationwith non-narcotic analgesics, antitussive preparations which containnarcotic or narcotic-like cough suppressants such as codeine,dihydrocodeinone, pholcodeine, and the like. Other products comprising anarcotic or narcotic-like composition for use as an antispasmodic in thegastro-intestinal tract, such as Camphorated Opium Tincture, U.S.P.,Opium Tincture, U.S.P., Opium extract, N.F., and the like may also beincluded.

Any desired amounts of the active substance may be used in theformulation described herein.

The term “ailment” is understood to be any physical or mental disorderor physical or mental disease; acute or chronic.

The term “maintenance dose” is referred to as the amount of activesubstance required to keep a desired mean steady-state concentration.For example, it is the amount of active substance administered tomaintain a desired level of the substance in the blood.

The term “loading dose” is defined as a dose of active substance, oftenlarger than subsequent doses, administered for the purpose ofestablishing a therapeutic level of the active substance.

The term “acid labile coat” refers to a coat comprising component(s)that will dissolve or degrade partially or completely, in an acidicenvironment (e.g. in a solution with an acidic pH). The acidic pH maybe, for example, below 7, below 6, below 5, below 4, below 3, below 2,or below 1. Typically, the pH at which the acid labile coat willdissolve is in the normal physiological pH of the stomach, such as fromabout 1 to about 5, from about 1 to about 4, or from about 2 to about 3.Typically, the acid labile coat dissolves or degrades more slowly or toa very low extent when in a solution with a pH that is considered notacidic. It will be understood that the acid labile coat may be preparedand designed to dissolve or degrade within any desired pH range and tonot dissolve substantially within any desired pH range. For example, theacid labile coat may be designed to dissolve at any pH below about 4 butabove that level, dissolution is inhibited, reduced or slowed. As the pHincreases, the dissolution may slow further and may stop nearlycompletely.

The acid labile coat typically contains an acid labile substance that isresponsible for the dissolution or degradation of the acid labile coatunder acidic conditions. For example, any suitable acid labile substanceused in the pharmaceutical industry may be used. Examples, without beinglimited thereto, of an acid labile substance include sulfonamide-basedpolymers and copolymers, amine functional polymers such as polyvinylpyridine polymers and copolymers, and polysaccharides such as chitosanthat are water-soluble at acidic pHs but water-insoluble at neutral orbasic pHs and poly (vinylpyrrolidone-co-dimethylmaleic anhydride) (PVD)that is water-soluble at neutral and acidic pHs but water-insoluble atbasic pHs. A typical example includes dimethylaminoethyl methacrylatecopolymers and derivatives thereof, such as Eudragit E, Eudragit Einterpolyelectrolyte complex, Eudragit E polyamopholyte complex, andEudragit E interpolyelectrolyte complex with Eudragit L and/or EudragitS. One of ordinary skill in the art could readily determine othermaterials that are water-insoluble at certain pHs but water-soluble atother pHs.

The term “base labile coat” refers to a coat comprising component(s)that will dissolve or degrade partially or completely, in a weaklyacidic, neutral or basic environment (e.g. in a solution with a basicpH). For example, the basic pH may be considered for the purposes hereinto be above 6, above 7, above 8, above 9, above 10, above 11, above 12,or above 13. Typically, the pH at which the base labile coat willdissolve is in the normal physiological pH of the duodenum, such as fromabout 6 to about 9, from about 6.5 to about 9, or from about 7 to about9. Typically, the base labile coat dissolves or degrades more slowly orto a very low extent when in a solution with a pH that is considered notbasic. It will be understood that the base labile coat may be preparedand designed to dissolve or degrade within any desired pH range and tonot dissolve substantially within any desired pH range. For example, thebase labile coat may be designed to dissolve at any pH above about 6 butbelow that level, dissolution is inhibited, reduced or slowed. As the pHdecreases, the dissolution may slow further and may stop nearlycompletely.

The base labile coat typically contains a base labile substance that isresponsible for the dissolution or degradation of the base labile coatunder basic conditions. For example, any suitable base labile substanceused in the pharmaceutical industry may be used. Examples, without beinglimited thereto, of an base labile substance include anypharmaceutically acceptable ethers, esters, ketones, epoxies, polyamidesand polysiloxanes that are water-soluble at neutral and basic pHs butwater-insoluble at acidic pHs. Any typical examples include any knownenteric coating(s) such as enteric polymers. For example, any anioniccopolymers based on methacrylic acid and methyl methacrylate. Examplesinclude Eudragit L or S. One of ordinary skill in the art could readilydetermine other materials that are water-insoluble at certain pHs butwater-soluble at other pHs.

The terms “alkalinizing agent,” “alkaline pH adjuster,” and “alkaline pHcontrol agent” may be used interchangeably and refer to substances thatare capable of modifying, controlling and/or adjusting the pH of theexternal or interior environment of a dosage form typically by makingthe environment have or maintain a basic pH or increase the pH. It alsorefers to basic substances and substances that can convert an acidicenvironment to a less acidic or basic environment. Typically, theseagents, when present in a sufficient amount, are able to raise the pH ofthe stomach to beyond physiological levels and thereby prevent, reduce,or inhibit dissolution of an acid labile substance described above.Examples of alkalinizing agents include basic salts, for example,alkaline earth metal and/or alkali metal salts such as magnesiumhydroxide, magnesium trisilicate magnesium oxide, calcium carbonate,sodium bicarbonate, sodium citrate, sodium carbonate, sodium acetate,magnesium carbonate, etc. Other examples include aluminum salts, such asaluminum oxide/hydroxides, any suitable amino acids or amino acidderivatives such as L-arginine or meglumine. Combinations of thealkalinizing agents may be used, including combinations of the exampleslisted. However, it will be understood that any agent capable ofdissolving and/or degrading and raising the pH of an acidic solution canbe used.

The term “alkalinizing coat” refers to a coat comprising alkalinizingagent(s) that will dissolve and/or degrade such that it is capable ofmodifying, controlling and/or adjusting the pH of the external orinterior environment of a dosage form typically by making theenvironment have or maintain a basic pH or increase the pH.

The terms “acidifying agent,” “acid pH adjuster,” and “acid pH controlagent” may be used interchangeably and refer to substances that arecapable of modifying, controlling and/or adjusting the pH of theexternal or interior environment of a dosage form typically by makingthe environment have or maintain an acid pH or decrease the pH. It alsorefers to acidic substances and substances that can convert a basicenvironment to a less basic or acidic environment. Typically, theseagents, when present in a sufficient amount, are able to lower the pH ofthe duodenum to beyond physiological levels and thereby prevent, reduce,or inhibit dissolution of a base labile substance described above.Examples of acidifying agents include, for example, inorganic andorganic acids. Examples include, but are not limited thereto,hydrochloric acid, sulfuric acid, nitric acid, lactic acid, phosphoricacid, citric acid, malic acid, fumaric acid, stearic acid, tartaricacid, boric acid, borax, and benzoic acid. Combinations of theacidifying agents may be used, including combinations of the exampleslisted. However, it will be understood that any agent capable ofdissolving and/or degrading and lowering the pH of a basic solution canbe used.

The term “acidifying coat” refers to a coat comprising acidifyingagent(s) that will dissolve and/or degrade such that it is capable ofmodifying, controlling and/or adjusting the pH of the external orinterior environment of a dosage form typically by making theenvironment have or maintain an acidic pH or decrease the pH.

The term “enteric coat” refers to a coat that is stable at the highlyacidic pH found in the stomach, but breaks down at a less acidic(relatively more basic) pH. For example, enteric coats will not dissolvein the stomach but they will in the basic pH environment present in thesmall intestine. Materials used for enteric coatings include polymerssuch as fatty acids, waxes, shellac, plastics, and plant fibers.

The term “Eudragit E” is referred to as a pH dependent polymer and, morespecifically, an acid labile polymer and may include anydimethylaminoethyl methacrylate copolymers. Examples include, but arenot limited to, Eudragit E™ and Eudragit E100™. The term “Eudragit RL”is referred to as a pH independent polymer and may be any poly(ethylacrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylatechloride. Examples include, but are not limited to, Eudragit RL™,Eudragit RL100™ Eudragit™ RL PO, Eudragit™ RL 30 D, and Eudragit™ RL12,5.

The terms “Eudragit NE”, “Eudragit RS” and “Eudragit NM” are referred toas pH independent polymers and may be any neutral copolymer based onethyl acrylate and methyl methacrylate. Examples include, but are notlimited to, Eudragit™ NE 30 D, Eudragit™ NE 40 D, and Eudragit™ NM 30 D,Eudragit™ RS 100, Eudragit™ RS PO, Eudragit™ RS 30 D, and Eudragit™ RS12,5.

The terms “Eudragit L” and “Eudragit S” are referred to as entericpolymers and may be any anionic copolymers based on methacrylic acid andmethyl methacrylate. Examples include Eudragit™ L 100, Eudragit™ L 12,5,Eudragit™ S 12,5 and Eudragit™ S 100. The ratio of the free carboxylgroups to the ester groups is approx. 1:1 in Eudragit™ L 100 and approx.1:2 in Eudragit™ S 100.

The terms “low”, “small” or “fine” particle size are interchangeable andrefer to sizes lower than 1500 microns.

The terms “large”, “high” or “big” surface area with respect to surfacearea of the active ingredients or excipients as a population ofparticles, powder, crystals, granules etc. are interchangeable and referto surface areas up to 10000 m²/g or higher.

The term “coat” may be variously characterized as a coating, layer,membrane, film, shell, capsule, or the like, and may partially,substantially or completely surround or envelope. For example, the“coat” may cover portions of the surface to which it is applied; e.g. asa partial layer, partial coating, partial membrane, partial film, orpartial shell; it may, for example, be in the form of half spheres thatcover the surface.

If the term “surrounding” is used alone, without any qualifier, it isunderstood to mean “at least partially surrounding”.

The term “controlled release” may be variously characterized by“sustained release”, “sustained action”, “extended release”, “modifiedrelease”, “pulsed release”, “delayed release”, “targeted release”, “sitespecific release”, and “timed release”, which are used interchangeablyin this application and are defined for purposes of the presentinvention as the time of release, the extent of release, the rate ofrelease, the site of release and/or release of an active ingredient froma formulation at such a rate that when a dose of the active ingredientis administered in the sustained release, extended release, pulsedrelease, timed release, delayed release or controlled-releaseformulation, concentrations (levels) of the active ingredient aremaintained within a desired range but below toxic levels over a selectedperiod of time. In the case of in vivo administration, concentrations(levels) of the active ingredient could be measured in blood or plasma,for example. When administered in vivo the sustained release, extendedrelease, pulsed release, timed release, delayed release orcontrolled-release formulation allows for a timely onset of action anduseful plasma concentration of an active ingredient to be maintained forlonger than in the case of immediate-release forms.

The expressions “such as”, “for example”, and “e.g.” means examples,without being limited thereto.

The term “polymeric coating” or “polymeric coat” means any coating,which is formed from materials such as resins, pharmaceutical polymersor from materials formed by polymerization of one or more monomers toform linear or branched or cross-linked macromolecules.

The term “functional coating” as used herein is defined to mean acoating that affects the rate of release in-vitro or in-vivo of theactive drug(s).

The term “non-functional coat” is defined to mean a coating that doesnot substantially affect the rate of release in-vitro or in-vivo of theactive drug, but can enhance the chemical, biological, physicalstability characteristics, or the physical appearance of the modifiedrelease dosage form.

The term “onset time” or “onset of action” represents latency, that is,the time required for the drug to reach minimum effective concentrationor the time required for the drug to begin to elicit its action. It mayalso represent the time for complete release of the drug (e.g. loadingdose). A “quick onset of action” represents a short period of time, forexample, about 1 hour or less, for the drug to reach minimum effectiveconcentration.

The terms “non-enteric polymer” and “pH independent polymer” are hereunderstood to refer to a polymer which is non-enteric, i.e., which isnot more soluble in non-acidic media than in acidic media. The terms“non-enteric polymer” and “pH independent polymer” therefore encompasspolymers which are equally soluble in acidic, and neutral or basicmedia. The terms “non-enteric polymer” and “pH independent polymer” mayadditionally encompass polymers which are more soluble in acidic mediathan in neutral or basic media and/or swellable in non-acidic media.

The term “mixture” is understood to include a combination of components,not necessarily mixed per se. The terms “mixture” and “combination” maybe used interchangeably.

The term “bittering agent” includes a compound used to impart a bittertaste, bitter flavor, etc.

The term “inhibit” refers to partially, substantially, or completelyslowing, hindering, reducing, delaying or preventing. The terms inhibit,reduced, prevented, delayed, and slowed may be used interchangeably.

The term “process variable” is understood to include anyphysical/chemical variable of a fluid media; for example, and withoutbeing limited thereto, at least one physical/chemical property of fluidmedia such as enzyme concentration, pK_(a), pK_(b), fat/triglyceridescontent, polarity (e.g. ionic strength), pH, density, temperature,solubility (K_(sp)), etc.

The term “threshold” or “setpoint” is understood to include at least onepredetermined value for the process variable; for example, at least onepredetermined value associated with at least one physical/chemicalproperty such as enzyme concentration, pK_(a), pK_(b), fat/triglyceridescontent, dielectric constant/strength, pH number or range, density orrange, temperature or range, solubility (K_(sp)), etc.

The term “regulator” is understood to include any pharmaceuticalacceptable additive that is capable of reacting with fluid media toadjust/regulate a process variable of a fluid media; examples includephysical/chemical barrier(s) including pH independent additives such asalkalinizing agents, alkalinizing coats, acidifying agents, andacidifying coats, additive(s) that undergo chemicaldecomposition/reaction (e.g. breaks down, dissolves, etc.) in accordancewith exposure to a fluid media (e.g. fluids in the digestive tract, suchas the stomach and duodenum) in order to adjust/regulate the processvariable of the fluid media to reach a threshold or setpoint, polymericmaterials, etc.

The term “actuator” is understood to include any pharmaceuticallyacceptable additive that is capable of reacting with fluid media at apre-determined threshold or setpoint; examples include physical/chemicalbarrier(s) including pH dependent additives such as acid labilesubstances, acid labile coats, base labile substances, and base labilecoats, additive(s) that undergo chemical decomposition/reaction (e.g.breaks down, dissolves, etc.) in accordance with exposure to a fluidmedia (e.g. fluids in the digestive tract, such as the stomach andduodenum), polymeric materials, etc.

The term “physical/chemical barrier” is understood to include anypharmaceutically acceptable additive that is capable of acting as abarrier to selectively release an active substance; examples includeacid labile substances, acid labile substances coats, polymericmaterials, base labile substances, base labile substances coats,alkalinizing agents, alkalinizing coats, acidifying agents, andacidifying coats.

The term “abuse deterrent coloring agent” refers to any suitablepharmaceutically useful coloring agent that can act to deter drug abuse.Examples include Aluminum Lake dyes; Aluminum Lake Blue#1; FD&C Blue No.1—Brilliant Blue FCF, E133 (blue shade); FD&C Blue No. 2—Indigotine;E132 (indigo shade); FD&C Green No. 3—Fast Green FCF, E143 (turquoiseshade); FD&C Red No. 3—Erythrosine, E127 (pink shade, commonly used inglac6 cherries); FD&C Red No. 40—Allura Red AC, E129 (red shade); FD&CYellow No. 5—Tartrazine, E102 (yellow shade); FD&C Yellow No. 6—SunsetYellow FCF, E110 (orange shade); E100 Curcumin (from turmeric),Yellow-orange; E101 Riboflavin (Vitamin B₂), formerly calledlactoflavin, Yellow-orange; Ell01a, Riboflavin-5′-Phosphate,Yellow-orange; E102, Tartrazine (FD&C Yellow 5), Lemon yellow; E103,Alkannin, Red-brown; E104, Quinoline Yellow WS, Dull or greenish yellow;E105, Fast Yellow AB, Yellow; E106, Riboflavin-5-Sodium Phosphate,Yellow; E107, Yellow 2G, Yellow; E110, Sunset Yellow FCF (Orange YellowS, FD&C Yellow 6), Yellow-orange; E111, Orange GGN, Orange; E120,Cochineal, Carminic acid, Carmine (Natural Red 4), Crimson; E121, CitrusRed 2, Dark red; E122, Carmoisine (azorubine), Red to maroon; E123,Amaranth (FD&C Red 2), Dark red; E124, Ponceau 4R (Cochineal Red A,Brilliant Scarlet 4R), Red; E125, Ponceau SX, Scarlet GN, Red; E126,Ponceau 6R, Red; E127, Erythrosine (FD&C Red 3), Red; E128, Red 2G, Red;E129, Allura Red AC (FD&C Red 40), Red; E130, Indanthrene blue RS, Blue;E131, Patent Blue V, Dark blue; E132, Indigo carmine (indigotine, FD&CBlue 2), Indigo; E133, Brilliant Blue FCF (FD&C Blue 1), Reddish blue;E140, Chlorophylls and Chlorophyllins: (i) Chlorophylls (ii)Chlorophyllins, Green; E141, Copper complexes of chlorophylls andchlorophyllins (i) Copper complexes of chlorophylls (ii) Coppercomplexes of chlorophyllins, Green; E142, Green S, Green; E143, FastGreen FCF (FD&C Green 3), Sea green; E150a, Plain caramel, Brown; E150b,Caustic sulphite caramel, Brown; E150c, Ammonia caramel, Brown; E150d,Sulphite ammonia caramel, Brown; E151, Black PN, Brilliant Black BN,Black; E152, Carbon black (hydrocarbon), Black; E153, Vegetable carbon,Black; E154, Brown FK (kipper brown), Brown; E155, Brown HT (chocolatebrown HT), Brown; E160a, Alpha-carotene, Beta-carotene, Gamma-carotene,Yellow-orange to brown; E160b, Annatto, bixin, norbixin, Orange; E160c,Paprika oleoresin, Capsanthin, capsorubin, Red; E160d, Lycopene, Brightto deep red; E160e, Beta-apo-8′-carotenal (C 30), Orange-red to yellow;E160f, Ethyl ester of beta-apo-8′-carotenic acid (C 30), Orange-red toyellow; E161a, Flavoxanthin, Golden-yellow and brownish; E161b, Lutein,Orange-red to yellow; E161c, Cryptoxanthin, Orange-red; E161d,Rubixanthin, Orange-red; E161e, Violaxanthin, Orange; E161f,Rhodoxanthin, Purple; E161g, Canthaxanthin, Violet; E161h, Zeaxanthin,Orange-red; E161i, Citranaxanthin, Deep violet E161j, Astaxanthin, Red;E162, Beetroot Red, Betanin, Red; E163, Anthocyanins, pH dependent (Red,green and purple ranges); E164, Saffron, Orange-red; E170, Calciumcarbonate, Chalk, White; E171, Titanium dioxide, White; E172, Ironoxides and iron hydroxides, Brown; E173, Aluminium, Silver to grey;E174, Silver, Silver; E175, Gold, Gold; E180, Pigment Rubine, LitholRubine BK, Red; E181, Tannin, Brown; E182, Orcein, Orchil, Purple.

The terms “disorders” and “diseases” are used inclusively and refer toany deviation from the normal structure or function of any part, organor system of the body (or any combination thereof). A specific diseaseis manifested by characteristic symptoms and signs, includingbiological, chemical and physical changes, and is often associated witha variety of other factors including, but not limited to, demographic,environmental, employment, genetic and medically historical factors.Certain characteristic signs, symptoms, and related factors can bequantitated through a variety of methods to yield important diagnosticinformation.

The condition, disease or disorder can be, e.g., pain, an age-associateddisorder, a geriatric disorder, a disorder having an age-associatedsusceptibility factor, a neoplastic disorder, a non-neoplastic disorder,a neurological disorder, a cardiovascular disorder, a metabolicdisorder, a dermatological disorder, or a dermatological tissuecondition. Examples include hypertension, angina, diabetes, HIV AIDS,pain, depression, psychosis, microbial infections, gastro esophagealreflux disease, impotence, cancer, cardiovascular diseases,gastric/stomach ulcers, blood disorders, nausea, epilepsy, Parkinson'sdisease, obesity, malaria, gout, asthma, erectile dysfunction,impotence, urinary incontinence, irritable bowel syndrome, ulcerativecolitis, smoking, arthritis, rhinitis, Alzheimer's disease, attentiondeficit disorder, cystic fibrosis, anxiety, insomnia, headache, fungalinfection, herpes, hyperglycemia, hyperlipidemia, hypotension, highcholesterol, hypothyroidism, infection, inflammation, mania, menopause,multiple sclerosis, osteoporosis, transplant rejection, schizophrenia,neurological disorders. Inflammatory conditions that may or may notcause pain. Such conditions may show one or more of the followingsymptoms: redness, heat, tenderness and swelling. Examples of suchconditions include, but are not limited to, chronic inflammatorydiseases, such as rheumatoid arthritis, inflammatory bowel disease,systemic lupus erythematosus, multiple sclerosis, and type I and IIdiabetes, asthma, and inflammatory diseases of the central nervoussystem such as multiple sclerosis, abscess, meningitis, encephalitis andvasculitis. Examples of cardiovascular conditions associated with painand/or inflammation include, but are not limited to, angina, arrhythmia,high blood pressure, stroke, congestive heart failure, atherosclerosis,peripheral artery diseases, high cholesterol levels, and heart attacks.Other disordere/conditions include Neurological or neurodegenerativecondition or a mental or behavioral disorder. Examples of neurologicalconditions associated with pain and/or inflammation include, but are notlimited to, Alzheimer's disease, amnesia, Aicardi syndrome, amyotrophiclateral sclerosis (Lou Gehrig's disease), anencephaly, anxiety, aphasia,arachnoiditis, Arnold Chiari malformation, attention deficit syndrome,autism, Batten disease, Bell's Palsy, bipolar syndrome, brachial plexusinjury, brain injury, brain tumors, childhood depresses ion,Charcol-Marie tooth disease, depression, dystonia, dyslexia,encephalitis, epilepsy, essential tremor, Guillain-Barre syndrome,hydrocephalus, hyperhidrosis, Krabbes disease, learning disabilities,leukodystrophy, meningitis, Moebius syndrome, multiple sclerosis,muscular dystrophy, Parkinson's disease, peripheral neuropathy,obsessive compulsive disorder, postural orthostatic tachycardiasyndrome, progressive supranuclear palsy, prosopagnosia, schizophrenia,shingles, Shy-Drager syndrome, spasmodic torticollis, spina bifida,spinal muscular atrophy, stiff man syndrome, synesthesia, syringomyelia,thoracic outlet syndrome, tourette syndrome, toxoplasmosis, andtrigeminal neurolagia. Examples of mental and behavioral disordersinclude, but are not limited to, anxiety disorder, panic disorder,obsessive-compulsive disorder, post-traumatic stress disorder, socialphobia (or social anxiety disorder), specific phobias, and generalizedanxiety disorder. Any of the above conditions can also be accompanied byor manifested by other conditions such as depression, drug abuse, oralcoholism. Examples of neoplastic growth include, but are not limitedto, breast cancer, skin cancer, bone cancer, prostate cancer, livercancer, lung cancer, brain cancer, cancer of the larynx, gallbladder,pancreas, rectum, parathyroid, thyroid, adrenal, neural tissue, head andneck, colon, stomach, bronchi, kidneys, basal cell carcinoma, squamouscell carcinoma of both ulcerating and papillary type, metastatic skincarcinoma, osteo sarcoma, Ewing's sarcoma, reticulum cell sarcoma,myeloma, giant cell tumor, small-cell lung tumor, gallstones, islet celltumor, primary brain tumor, acute and chronic lymphocytic andgranulocytic tumors, hairy-cell leukemia, adenoma, hyperplasia,medullary carcinoma, pheochromocytoma, mucosal neuronms, intestinalganglioneuromas, hyperplastic corneal nerve tumor, marfanoid habitustumor, Wilm's tumor, seminoma, ovarian tumor, leiomyomater tumor,cervical dysplasia and in situ carcinoma, neuroblastoma, retinoblastoma,soft tissue sarcoma, malignant carcinoid, topical skin lesion, mycosisfungoide, rhabdomyosarcoma, Kaposi's sarcoma, osteogenic and othersarcoma, malignant hypercalcemia, renal cell tumor, polycythermia vera,adenocarcinoma, glioblastoma multiforme, leukemias, lymphomas, malignantmelanomas, epidermoid carcinomas, and other carcinomas and sarcomas.

Oral Drug Delivery Formulations, Uses Thereof and Methods of Making Same

Oral drug delivery formulations, uses thereof and methods of making sameare provided in order to reduce the potential for abuse, misuse orimproper administration of an addictive substance or any activesubstance and to prevent, reduce, inhibit, or delay purposeful oraccidental overdose of an active substance by ingesting too many pillsat once, for example.

In general, and in view of the many examples provided herein, the unitdose formulations may comprise at least one active substance, whereinrelease of the at least one active substance is inhibited when thenumber of unit dosage formulations ingested exceeds a predeterminednumber, such as a prescribed number of unit dosage formulations. Eachunit dose formulation comprises at least one active substance, at leastone actuator (e.g. a physical/chemical barrier such as a pH dependentcoat) and at least one regulator (e.g. a physical/chemical barrier suchas a pH independent coat). When the unit dose formulation is exposed toa fluid media having a certain process variable (e.g. pH), and apredetermined threshold or setpoint (e.g. pH number or range) isestablished for the variable, the regulator is capable of adjusting thevariable (e.g. depending on the number of unit dosage formulationsprovided and the amount of regulator present in the formulation) andcontrol the release of the active substance via the actuator. Forexample, where it is desired for the active substance to be released inan acidic media, the setpoint would be the desired acidic pH rangerequired for such a release. If there is a predetermined number of unitdosage formulations provided, the regulator would dissolve in the acidicmedia and the actuator would be actuated by the acidic media and permitthe release of the active substance. If the number of unit dosageformulations ingested exceeds the predetermined number, the amount ofregulator would dissolve in the acidic media, cause the pH of the mediato increase above the setpoint, which would, for example, cause a lagtime, delayed release, no release or insignificant release of the activesubstance. In another example, where it is desired for the activesubstance to be released in a basic media, the setpoint would be thedesired basic pH range required for such a release. If there is apredetermined number of unit dosage formulations provided, the regulatorwould dissolve in the basic media and the actuator would be actuated bythe basic media and permit the release of the active substance. If thenumber of unit dosage formulations ingested exceeds the predeterminednumber, the regulator would dissolve in the basic media, cause the pH ofthe media to decrease below the setpoint, which would, for example,cause a lag time, delayed release, no release or insignificant releaseof the active substance.

In some embodiments, the formulations contain a core surrounded by atleast two coats, referred to as an inner coat and an outer coat. It willbe understood that additional coats may exist, between or on either sideof the inner and/or outer coat, and these are merely referred to as theinner and outer coat in relation to one another. The active substancemay be included in the core and/or coat.

The type of inner and outer coats chosen is dependent on where theactive substance is to be released in the body. For example, and withoutbeing limited thereto, whether the active substance(s) is released in anacidic environment (e.g. stomach) or a basic or less acidic environment(e.g. duodenum).

In one aspect, if the active substance is to be released in the stomach,the core contains the active substance and the inner coat completelysurrounds the core. The inner coat contains an acid labile substance sothat the inner coat will only dissolve and allow release of the activesubstance in an acidic environment. The outer coat surrounds the innercoat and comprises an alkalinizing agent. The alkalinizing agentdissolves in aqueous solution in a pH-independent manner.

When a single unit dosage formulation, for example, is ingested, thealkalinizing agent dissolves but is in an insufficient amount to raisethe pH of the stomach enough to prevent dissolution of the coatcontaining the acid labile substance. In this case, the acid labile coatwill dissolve and the active substance will be released. However, whenmultiple unit dosage forms are ingested simultaneously or within acertain amount of time, for example, within about 1 hour or less, suchas within about 45 minutes, 30 minutes, 20 minutes, 10 minutes, or 5minutes, several alkalinizing coats will dissolve, providing sufficientalkalinizing agent to raise the pH of the stomach enough to prevent orslow dissolution of the acid labile coat. In this case, release of theactive substance is prevented, reduced, inhibited and/or slowed. Inother aspects of the embodiments described above, the active substancemay be additionally or solely in a separate coat and/or in other coats,such as the inner coat, as long as it maintains the physiological effectof preventing, reducing, inhibiting and/or slowing release of the activesubstance when more than the recommended or prescribed number of unitdosage forms is ingested simultaneously or within a certain amount oftime. Typically, the active substance may be in a separate coatsurrounding the core (between the core and the inner coat) and/or in theinner coat.

In another aspect, if the active substance is to be released in theduodenum, there are at least three coats surrounding the core: an innercoat, an intermediate coat, and an outer coat. The core contains theactive substance and the inner coat completely surrounds the core. Theinner coat contains a base labile substance so that the inner coat willonly dissolve and allow release of the active substance in a basicenvironment. The intermediate coat surrounds the inner coat andcomprises an acidifying agent. The acidifying agent dissolves in aqueoussolution in a pH-independent manner. The outer coat surrounds theintermediate coat and comprises a base labile substance so that the coatwill remain substantially intact so that it reaches the duodenum.

When a single unit dosage formulation, for example, is ingested, theouter coat with the base labile substance dissolves in the duodenum toexpose the intermediate coat comprising the acidifying agent. Theintermediate coat dissolves but is in an insufficient amount to lowerthe pH of the duodenum enough to prevent dissolution of the inner coatcontaining the base labile substance. In this case, the inner baselabile coat will dissolve and the active substance will be released.However, when multiple unit dosage forms are ingested simultaneously orwithin a certain amount of time, for example, within about 1 hour orless, such as within about 45 minutes, 30 minutes, 20 minutes, 10minutes, or 5 minutes, several acidifying coats will dissolve, providingsufficient acidifying agent to lower the pH of the duodenum enough toprevent, reduce or slow dissolution of the inner base labile coat. Inthis case, release of the active substance is prevented, reduced,inhibited and/or slowed. In other aspects, the active substance may beadditionally or solely in a separate coat(s) and/or in other coats, suchas the inner coat, as long as it maintains the physiological effect ofpreventing, reducing, inhibiting and/or slowing release of the activesubstance when more than the recommended or prescribed number of unitdosage forms is ingested simultaneously or within a certain amount oftime. Typically, the active substance may be in a separate coatsurrounding the core (between the core and the inner coat) and/or in theinner coat. In general, the formulations provide the necessary amount ofa drug to the patient over a period of time in order to accomplish thedesired pharmaceutical effect (such as timely and adequate pain relief,inducing sleep, control of blood pressure and blood sugar levels, etc.),while decreasing or eliminating the problem of improper administrationof medications and their use in a non-indicated or non-prescribed mannerresulting in abuse, drug overdose, addiction, suboptimal efficacy, ordeath.

The formulations may additionally incorporate one or more insufflationdiscouraging agents in order to prevent, reduce, or inhibit abuse bycrushing and inhaling the unit dose formulation. For example, theformulation when perturbed, pulverized or crushed or ground or milled orcut into one or more sizes ranging from very fine to coarse particles,granules or spheres are inhaled or snorted a moderate to severediscomfort is triggered due to irritation and discomfort in the nostrilsand the airways and lungs which leads to dislike and helps to discouragefurther use or abuse.

In certain embodiments, the formulation comprises a core having at leastone active substance, and optionally at least one substance that can actto discourage insufflation of powder or granules or particles obtainedupon pulverization or milling of the intact formulation wherein the coreis surrounded first by an acid labile coat(s), which is furthersurrounded by an alkalinizing coat(s) or the core is surrounded first bya base labile coat(s), which is further surrounded by an acidifyingcoat(s), which is further surrounded by a base labile coat(s).

In other embodiments, the formulation comprises a core having at leastone active substance, and optionally at least one substance that can actto discourage insufflation of powder or granules or particles obtainedupon pulverization or milling of the intact formulation wherein the coreis surrounded first by a drug-releasing coat(s), which is furthersurrounded by an acid labile coat(s) followed by an alkalinizing coat(s)or the core is surrounded first by a base labile coat(s), which isfurther surrounded by an acidifying coat(s), which is further surroundedby a base labile coat(s).

In yet other embodiments, the formulation comprises a core havingoptionally at least one substance that can act to discourageinsufflation of powder or granules or particles obtained uponpulverization or milling of the intact formulation wherein the core issurrounded first by a drug-releasing coat(s), which is furthersurrounded by an acid labile coat(s) followed by an alkalinizing coat(s)or the core is surrounded first by a base labile coat(s), which isfurther surrounded by an acidifying coat(s), which is further surroundedby a base labile coat(s). In some other embodiments one or more of thecoats contain at least one substance that can act to discourageinsufflation.

In other aspects of the embodiments described above, the activesubstance may be additionally or solely in a separate coat(s) and/or inother coats, such as the inner coat, as long as it maintains thephysiological effect of preventing, reducing, inhibiting and/or slowingrelease of the active substance when more than the recommended orprescribed number of unit dosage forms is ingested simultaneously orwithin a certain amount of time. Typically, the active substance may bein a separate coat surrounding the core (between the core and the innercoat) and/or in the inner coat.

The formulations described herein may prevent, retard, reduce, inhibit,or at least not increase, significantly, the instantaneous release orrate of release of the drug substance from a formulation leading tooverdose when many unit dose forms of the product are taken intact andat once contrary to the prescribed instructions. The formulations thus,in some instances can prevent, retard, reduce, inhibit, or provide adelay of overdose and its untoward effects from improper administrationof a number of intact unit dose forms intentionally or otherwise, as thedrug will not be immediately and rapidly released from the formulation.This is demonstrated in the Examples 2, 4, and 6 below.

Certain formulations described herein are immediate releaseformulations, while certain other formulations are controlled releaseformulations and yet other formulations are combination products. Theformulations may be presented as tablets, capsules, beads,microcapsules, crystals, granules or a combination.

The acid labile coat contains an acid labile substance(s), such as aEudragit E polymer, in an amount of from about 0.1 wt % to about 99 wt %of the core or layer/coat, typically, from about 1 wt % to about 60 wt %or from about 5 wt % to about 50 wt %. The acid labile coat may providea coating coverage surface area, for example, of from 0.5 mg/cm² to 200mg/cm² or from 1 mg/cm² to 100 mg/cm² or from 2 mg/cm² to 150 mg/cm² orfrom about 4 mg/cm² to about 100 mg/cm² or from 8 mg/cm² to 50 mg/cm².The acid labile substance(s) may range from a ratio of 1:1000 to a ratioof 1000:1 of the core or layer/coat wt/wt. The acid labile substance(s)may also be present in the amounts of 0.1 to 500% of the composition byweight. In typical embodiments, the amount of the acid labilesubstance(s) is present of from about a minimum of 0.5 mg. Moretypically, from about 0.5 mg to about 500 mg, and any ranges or amountstherebetween, based on the weight of the composition.

The base labile coat contains a base labile substance(s), such as aEudragit L or S polymer, in an amount of from about 0.1 wt % to about 99wt % of the core or layer/coat, typically, from about 1 wt % to about 60wt % or from about 5 wt % to about 50 wt %. The base labile coat mayprovide a coating coverage surface area of from 0.5 mg/cm² to 200 mg/cm²or from 2 mg/cm² to 150 mg/cm² or from about 4 mg/cm² to about 100mg/cm².

The base labile substance(s) may range from a ratio of 1:1000 to a ratioof 1000:1 of the core or layer/coat wt/wt. The base labile substance(s)may also be present in the amounts of 0.1 to 500% of the composition byweight. In typical embodiments, the amount of the base labilesubstance(s) is present of from about a minimum of 0.5 mg. Moretypically, from about 0.5 mg to about 500 mg, and any ranges or amountstherebetween, based on the weight of the composition.

In another embodiment, there is provided a unit dose formulationcomprising a core comprising at least one active substance in an amountof from about 0.1 mg to about 1000 mg; at least one acid labile coat inan amount of from about 0.5 mg to about 500 mg surrounding the core; andat least one alkalinizing coat in an amount of from about 0.5 mg toabout 500 mg surrounding said at least one acid labile coat.

In another embodiment, there is provided a unit dose formulationcomprising a core comprising at least one active substance in an amountof from about 0.5 mg to about 1000 mg; at least one coat comprising atleast one active substance in an amount of from about 0.5 mg to about1000 mg; at least one acid labile coat in an amount of from about 0.5 mgto about 500 mg surrounding the core; and at least one alkalinizing coatin an amount of from about 0.5 mg to about 500 mg surrounding said atleast one acid labile coat.

In another embodiment, there is provided a unit dose formulationcomprising a core comprising at least one active substance and at leastone acid labile substance in an amount of from about 0.5 mg to about 500mg; and at least one alkalinizing coat in an amount of from about 0.5 mgto about 500 mg surrounding the core; at least one controlled releaseagent.

In other embodiments, the core is a mixture of components; typically, ahomogeneous mixture of components. For example, the core may comprise atleast one abuse deterrent coloring agent; at least one controlledrelease agent; at least one viscosity imparting agent; at least onegelling agent; polyethylene oxide; crospovidone; Eudragit RL and/or RS,or mixtures/combinations thereof.

In a specific embodiment, the core comprises at least one activesubstance and at least one abuse deterrent coloring agent.

In a specific embodiment, the core includes a homogeneous mixture ofsaid at least one active substance and at least one controlled releaseagent.

In a specific embodiment, the core includes a homogeneous mixture ofsaid at least one active substance and at least one viscosity impartingagent.

In a specific embodiment, the core includes a homogeneous mixture ofsaid at least one active substance and at least one gelling agent.

In a specific embodiment, the core includes a homogeneous mixture ofsaid at least one active substance and polyethylene oxide.

In a specific embodiment, the core includes a homogeneous mixture ofsaid at least one active substance and crospovidone.

In a specific embodiment, the core includes a homogeneous mixture ofsaid at least one active substance and Eudragit RL and/or RS.

In a specific embodiment, one or more than one coat includes at leastone abuse deterrent coloring agent.

Examples of the amounts of the components are as follows:

In a specific embodiment, the core includes a mixture of said at leastone active substance and from about 1 mg to about 400 mg of at least oneabuse deterrent coloring agent.

In a specific embodiment, the core includes a homogeneous mixture ofsaid at least one active substance and from about 4 mg to about 600 mgof at least one controlled release agent.

In a specific embodiment, the core includes a homogeneous mixture ofsaid at least one active substance and from about 2 mg to about 700 mgof at least one viscosity imparting agent.

In a specific embodiment, the core includes a homogeneous mixture ofsaid at least one active substance and from about 2 mg to about 1000 mgof at least one gelling agent.

In a specific embodiment, the core includes a homogeneous mixture ofsaid at least one active substance and from about 3 mg to about 1000 mgof polyethylene oxide

In a specific embodiment, the core includes a homogeneous mixture ofsaid at least one active substance and from about 0.5 mg to about 100 mgof crospovidone

In a specific embodiment, the core includes a homogeneous mixture ofsaid at least one active substance and from about 0.5 mg to about 100 mgof Eudragit RL and/or RS

In a specific embodiment, one or more coats includes from about 1 mg toabout 400 mg of at least one abuse deterrent coloring agent.

The core may comprise an inner matrix of at least one active substanceand an outer matrix of at least one active substance (e.g. an activesubstance release layer).

Such formulations described herein are capable of mitigating orpreventing overdose when the amount of a dosage form (e.g., tablets orcapsules) is taken over the prescribed or recommended level (amount) orwhen someone takes a higher dose than prescribed or recommended.

In some typical embodiments, the formulation may be a pharmaceuticalformulation having at least one coat of an acid labile substance(s),such as Eudragit E, over-coated with at least one coat of analkalinizing agent(s).

Some of the formulations may contain an opioid antagonist such asnaltrexone in the core or one or more of the coats. The formulationsdescribed herein are capable of preventing or mitigating overdose when adrug product or other substance is ingested or swallowed in quantitiesgreater than are recommended or generally practiced or in the case ofunintentional misuse via errors in dosage caused by failure to read orunderstand product labels, including accidental overdoses as a result ofover-prescription, failure to recognize a drug's active ingredient, orunwitting ingestion by children.

As discussed above, the formulations described may also containsubstances that can make the formulations more objectionable toinsufflation upon being pulverized or crushed or ground or milled or cutinto one or more sizes ranging from very fine to coarse particles,granules or spheres. As such the formulations are designed to discourageinsufflation of pulverized or crushed or ground or milled or cut intoone or more sizes ranging from very fine to coarse particles, granulesor spheres.

In an embodiment, the formulation comprises i) at least one activesubstance, ii) Eudragit E (dimethylaminoethyl methacrylate copolymer andthe like), iii) one or more alkalinizing agents and optionally iv)substances such as sodium lauryl sulfate and/or other irritants.

In a specific embodiment, the formulation comprises i) at least oneactive substance in the core, which is surrounded by ii) at least onecoating for controlling the release of the active substance(s), whereinat least one of the coating(s) contains Eudragit E (dimethylaminoethylmethacrylate copolymer) and, surrounded by iii) at least one coating foralkalinizing or adjusting or controlling the pH of either the internalor external or both of the environments of the compositions, wherein atleast one of the coating(s) contains one or more alkalinizing agentssuch as magnesium hydroxide, magnesium trisilicate, magnesium oxide,sodium bicarbonate, magnesium carbonate, sodium hydroxide, aluminiumhydroxide, calcium carbonate, and other metal hydroxides and basicoxides and substances that can react alone or together and optionallyiv) substances such as sodium lauryl sulfate and/or irritants such ascapsaicin oleoresin present in either or all of the core or coats.

In another embodiment, the amount of acid labile substance andalkalinizing agent in the coats makes the formulation/compositions moredifficult to be inadvertently or deliberately overdosed when ingestedintact or abused when subdivided. In a further embodiment, theformulation comprises at least one primary active substance, at leastone acid labile coat, and at least one alkalinizing coat wherein theformulation is free of any active substance external to the coat.

In a further embodiment, the formulation comprises i) at least oneactive substance in the core, or coat surrounding a core which issurrounded by ii) at least one coating for controlling the release ofthe active substance(s), wherein at least one of the coating(s) containsEudragit E (dimethylaminoethyl methacrylate copolymer) and, surroundedby iii) at least one coating for alkalinizing or adjusting orcontrolling the pH of either the internal or external or both of theenvironments of the compositions, wherein at least one of the coating(s)contains one or more alkalinizing agents such as magnesium hydroxide,magnesium trisilicate, magnesium oxide, sodium bicarbonate, magnesiumcarbonate, sodium hydroxide, aluminium hydroxide, calcium carbonate, andother metal hydroxides and basic oxides and substances that can reactalone or together and optionally iv) one or a combination of irritantsor tussigenic substances such as sodium lauryl sulfate, capsaicinoleoresin, citric acid, tartaric acid or their derivatives present ineither or all of the core or coats.

In yet a further embodiment, the formulation comprises i) at least oneactive substance in the core, or coat surrounding a core which issurrounded by ii) at least one coating for controlling the release ofthe active substance(s), wherein at least one of the coating(s) containsEudragit E (dimethylaminoethyl methacrylate copolymer) and, thistogether with at least one or more alkalinizing agent or adjusting orcontrolling the pH of for modifying either the internal or external orboth of the environments of the compositions, wherein at least one ormore of the alkalinizing agents and/or pH adjusters and/or pH controlagents is magnesium hydroxide, magnesium trisilicate, magnesium oxide,sodium bicarbonate, magnesium carbonate, sodium hydroxide, aluminiumhydroxide, calcium carbonate, and other metal hydroxides and basicoxides and substances that can react alone or together and optionallyone or a combination of irritants or tussigenic substances such assodium lauryl sulfate, capsaicin oleoresin, citric acid, tartaric acidor their derivatives are placed in a housing such as a hard gelatin orhydroxyl propyl methyl cellulose capsule, or sachets or bottles and thelike.

In a specific embodiment, the formulation comprises at least one activesubstance; at least one coat comprising Eudragit E (dimethylaminoethylmethacrylate copolymer); and at least one alkalinizing coat.

In a further embodiment, the formulation comprises at least one activesubstance; at least one polyethylene oxide; at least one disintegrant;at least one Eudragit RL and Eudragit RS; optionally at least onecoloring agent; at least one coat comprising Eudragit E(dimethylaminoethyl methacrylate copolymer); and at least onealkalinizing coat.

In a further embodiment, the formulation comprises at least one activesubstance; at least one acid labile coat, the solubility of which isdependent on the concentration of at least one alkalinizing agent in atleast one alkalinizing coat; and the at least one alkalinizing coat.

In a further embodiment, the formulation comprises at least one activesubstance; at least one polyethylene oxide; at least one disintegrant;at least one Eudragit RL and Eudragit RS; optionally a coloring agent;at least one acid labile coat, the solubility of which is dependent onthe concentration of at least one alkalinizing agent in at least onealkalinizing coat; and the at least one alkalinizing coat.

In a further embodiment, the formulation comprises at least one activesubstance; at least one acid labile coat, the solubility of which isdependent on the concentration of at least one alkalinizing agent in atleast one alkalinizing coat; and the at least one alkalinizing coat.

In another embodiment, the formulation comprises at least one activesubstance; at least one polyethylene oxide; at least one disintegrant;at least one Eudragit RL and Eudragit RS; optionally a coloring agent;at least one acid labile coat, the solubility of which is dependent onthe concentration of at least one alkalinizing agent in at least onealkalinizing coat; and the at least one alkalinizing coat.

In a further embodiment, the formulation comprises at least one activesubstance; at least polyethylene oxide; at least a disintegrant; atleast Eudragit RL or RS; optionally a coloring agent; at least one coatthat is soluble in stomach pH, the solubility of which is dependent onthe concentration of at least one alkalinizing agent; and at least onecoat comprising said at least one alkalinizing agent.

In a further embodiment, the formulation comprises at least one activesubstance; at least one polyethylene oxide; at least one disintegrant;at least one Eudragit RL and Eudragit RS; optionally a coloring agent;at least one coat that is soluble in stomach pH, the solubility of whichis dependent on the concentration of at least one alkalinizing agent inat least one alkalinizing coat; and the at least one alkalinizing coat.

In a further embodiment, the formulation comprises at least one activesubstance; at least one coat that is soluble in stomach pH, thesolubility of which decreases in the presence of increasingconcentrations of at least one alkalinizing agent in at least onealkalinizing coat; and the at least one alkalinizing coat.

In a further embodiment, the formulation comprises at least one activesubstance; at least one polyethylene oxide; at least one disintegrant;at least one Eudragit RL or Eudragit RS; optionally a coloring agent; atleast one coat that is soluble in stomach pH, the solubility of whichdecreases in the presence of increasing concentrations of at least onealkalinizing agent in at least one alkalinizing coat; and the at leastone alkalinizing coat.

With respect to the embodiments described above regarding formulaedesigned for release in the stomach, similar embodiments can be designedfor release in the duodenum, whereby the alkalinizing agent is replacedwith an acidifying agent and the acid labile coat is replaced with abase labile coat; and a further outer base labile coat is added.

In certain embodiments, when more than one intact unit (such as a tabletor capsule) or quantities greater than are recommended or prescribed ofthe formulation/composition is ingested at once or in the case ofunintentional misuse via errors in dosage caused by failure to read orunderstand product labels, including accidental overdoses as a result ofover-prescription, failure to recognize a drug's active ingredient, orunwitting ingestion by children, there is no instantaneous release ofall of the active or insignificant amount (e.g. non-life threateningamount) of the active is released over a given period of time. Theformulations/compositions, in the embodiments prevent, reduce, inhibitand/or delay overdose or suicide from occurring when more tablets orcapsules of an immediate release or controlled release medication thanprescribed are taken at once by mouth.

In other embodiments, the formulation delays, inhibits, or prevents theinstantaneous release of all or significant amounts of active substancewhen greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 unit dose forms areswallowed intact, such as between 2 to 10 unit dose forms, or between 11to 20 unit dose forms, or between 21 to 30 unit dose forms, or between31 to 40 unit dose forms, or between 41 to 50 unit dose forms, orbetween 51 to 100 unit dose forms, or greater than 100 unit dose formsof a medication are swallowed intact.

In another embodiment, a formulation contains Oxycodone (e.g. from about1 mg to about 500 mg). The formulation delays, inhibits, or prevents theinstantaneous release of all or significant amounts of oxycodone whengreater than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 unit dose forms areswallowed intact, such as between 2 to 10 unit dose forms, or between 11to 20 unit dose forms, or between 21 to 30 unit dose forms, or between31 to 40 unit dose forms, or between 41 to 50 unit dose forms, orbetween 51 to 100 unit dose forms, or greater than 100 unit dose formsof a medication are swallowed intact.

In another embodiment, a formulation contains Hydrocodone (e.g. fromabout 1 mg to about 500 mg). The formulation delays, inhibits, orprevents the instantaneous release of all or significant amounts ofhydrocodone when greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 unit doseforms are swallowed intact, such as between 2 to 10 unit dose forms, orbetween 11 to 20 unit dose forms, or between 21 to 30 unit dose forms,or between 31 to 40 unit dose forms, or between 41 to 50 unit doseforms, or between 51 to 100 unit dose forms, or greater than 100 unitdose forms of a medication are swallowed intact.

In another embodiment, a formulation contains Oxymorphone (e.g. fromabout 1 mg to about 500 mg). The formulation delays, inhibits, orprevents the instantaneous release of all or significant amounts ofOxymorphone when greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 unit doseforms are swallowed intact, such as between 2 to 10 unit dose forms, orbetween 11 to 20 unit dose forms, or between 21 to 30 unit dose forms,or between 31 to 40 unit dose forms, or between 41 to 50 unit doseforms, or between 51 to 100 unit dose forms, or greater than 100 unitdose forms of a medication are swallowed intact.

In another embodiment, a formulation contains Hydromorphone (e.g. fromabout 1 mg to about 500 mg). The formulation delays, inhibits, orprevents the instantaneous release of all or significant amounts ofHydromorphone when greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 unitdose forms are swallowed intact, such as between 2 to 10 unit doseforms, or between 11 to 20 unit dose forms, or between 21 to 30 unitdose forms, or between 31 to 40 unit dose forms, or between 41 to 50unit dose forms, or between 51 to 100 unit dose forms, or greater than100 unit dose forms of a medication are swallowed intact.

In another embodiment, a formulation contains Codeine (e.g. from about 1mg to about 500 mg). The formulation delays, inhibits, or prevents theinstantaneous release of all or significant amounts of Codeine whengreater than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 unit dose forms areswallowed intact, such as between 2 to 10 unit dose forms, or between 11to 20 unit dose forms, or between 21 to 30 unit dose forms, or between31 to 40 unit dose forms, or between 41 to 50 unit dose forms, orbetween 51 to 100 unit dose forms, or greater than 100 unit dose formsof a medication are swallowed intact.

In another embodiment, a formulation contains Morphine (e.g. from about1 mg to about 500 mg). The formulation delays, inhibits, or prevents theinstantaneous release of all or significant amounts of Morphine whengreater than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 unit dose forms areswallowed intact, such as between 2 to 10 unit dose forms, or between 11to 20 unit dose forms, or between 21 to 30 unit dose forms, or between31 to 40 unit dose forms, or between 41 to 50 unit dose forms, orbetween 51 to 100 unit dose forms, or greater than 100 unit dose formsof a medication are swallowed intact.

In another embodiment, a formulation contains Oxycodone (e.g. from about1 mg to about 500 mg) in combination with Acetaminophen or other NSAIDs(e.g. from about 50 mg to about 900 mg). The formulation delays,inhibits, or prevents the instantaneous release of all or significantamounts of oxycodone and/or Acetaminophen and/or NSAIDs when greaterthan 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 unit dose forms are swallowedintact, such as between 2 to 10 unit dose forms, or between 11 to 20unit dose forms, or between 21 to 30 unit dose forms, or between 31 to40 unit dose forms, or between 41 to 50 unit dose forms, or between 51to 100 unit dose forms, or greater than 100 unit dose forms of amedication are swallowed intact.

In another embodiment, a formulation contains Hydrocodone (e.g. fromabout 1 mg to about 500 mg) in combination with Acetaminophen or otherNSAIDs (e.g. from about 50 mg to about 900 mg). The formulation delays,inhibits, or prevents the instantaneous release of all or significantamounts of hydrocodone and/or Acetaminophen and/or NSAIDs when greaterthan 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 unit dose forms are swallowedintact, such as between 2 to 10 unit dose forms, or between 11 to 20unit dose forms, or between 21 to 30 unit dose forms, or between 31 to40 unit dose forms, or between 41 to 50 unit dose forms, or between 51to 100 unit dose forms, or greater than 100 unit dose forms of amedication are swallowed intact.

In another embodiment, a formulation contains Oxymorphone (e.g. fromabout 1 mg to about 500 mg) in combination with Acetaminophen or otherNSAIDs (e.g. from about 50 mg to about 900 mg). The formulation delays,inhibits, or prevents the instantaneous release of all or significantamounts of Oxymorphone and/or Acetaminophen and/or NSAIDs when greaterthan 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 unit dose forms are swallowedintact, such as between 2 to 10 unit dose forms, or between 11 to 20unit dose forms, or between 21 to 30 unit dose forms, or between 31 to40 unit dose forms, or between 41 to 50 unit dose forms, or between 51to 100 unit dose forms, or greater than 100 unit dose forms of amedication are swallowed intact.

In another embodiment, a formulation contains Hydromorphone (e.g. fromabout 1 mg to about 500 mg) in combination with Acetaminophen or otherNSAIDs (e.g. from about 50 mg to about 900 mg). The formulation delays,inhibits, or prevents the instantaneous release of all or significantamounts of Hydromorphone and/or Acetaminophen and/or NSAIDs when greaterthan 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 unit dose forms are swallowedintact, such as between 2 to 10 unit dose forms, or between 11 to 20unit dose forms, or between 21 to 30 unit dose forms, or between 31 to40 unit dose forms, or between 41 to 50 unit dose forms, or between 51to 100 unit dose forms, or greater than 100 unit dose forms of amedication are swallowed intact.

In another embodiment, a formulation contains Codeine (e.g. from about 1mg to about 500 mg) in combination with Acetaminophen or other NSAIDs(e.g. from about 50 mg to about 900 mg). The formulation delays,inhibits, or prevents the instantaneous release of all or significantamounts of Codeine and/or Acetaminophen and/or NSAIDs when greater than1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 unit dose forms are swallowed intact,such as between 2 to 10 unit dose forms, or between 11 to 20 unit doseforms, or between 21 to 30 unit dose forms, or between 31 to 40 unitdose forms, or between 41 to 50 unit dose forms, or between 51 to 100unit dose forms, or greater than 100 unit dose forms of a medication areswallowed intact.

Formulations Objectionable to Tampering, Chewing, Sucking, Lickingand/or Holding in the Mouth

A bittering agent may optionally be present in the formulations to makethe compromised formulation objectionable to chewing, sucking, lickingand/or holding in the mouth. The pharmaceutically acceptable bitteringagents used may be denatonium benzoate, denatonium, saccharide esterssuch as sucrose octaacetate, naringin, phenylglucopyranose, benzylglucopyranose, tetramethylglucose and glucose pentaacetate, or quassin.The most typical is sucrose octaacetate. With the inclusion of, forexample, from about 0.00001 mg to about 100 mg per tablet or unit dosageform of a bittering agent in a formulation, when the formulation istampered with, the bittering agent imparts a discomforting quality tothe abuser to typically discourage the inhalation or oral administrationof the tampered formulation, and typically to prevent the abuse of theformulation.

Suitable bittering compositions may include bittering agents oranalogues thereof in a concentration 20 to 1000 ppm, typically 10 to 500ppm and most typically 5 to 100 ppm in the finished product.

In an embodiment, the formulation comprises a core containing one ormore active substance(s) with or without a bittering agent, surroundedby an acid labile coat, which is then surrounded by an alkalinizingcoat. In another embodiment, the formulation comprises a core containingone or more active substance(s) with or without a bittering agent,surrounded by a base labile coat, which is then surrounded by anacidifying coat, followed by a further base labile coat. The coats canbe applied by spraying or dry coating or encapsulation or by acombination of these methods.

In certain embodiments, the formulation is objectionable to chewing,sucking, licking and/or holding in the mouth for more than about 1minute; for more than about 5 minutes, or for more than about 10minutes. In another embodiment, the formulation is objectionable tochewing, sucking, licking and/or holding in the mouth for less thanabout 10 minutes but greater than about 30 seconds. Moreover, in similarembodiments, the formulation will not permit release or will not releasea significant amount of the active ingredient(s) in the pH environmentof the mouth.

An irritant or tussigenic agent may be present in the formulations. Inembodiments, from about 0.000001 mg to about 300 mg of the irritant ortussigenic agent may be present in the formulations. With the inclusionof an irritant (e.g., capsaicin) in the formulation, when theformulation is tampered with, the capsaicin imparts a burning ordiscomforting quality to the abuser to typically discourage theinhalation, injection, or oral administration of the tamperedformulation, and typically to prevent the abuse of the formulation.Suitable capsaicin compositions include capsaicin (trans8-methyl-N-vanillyl-6-noneamide) or analogues thereof in a concentrationbetween about 0.00125% and 50% by weight, typically between about 1 andabout 7.5% by weight, and most typically, between about 1 and about 5%by weight of the formulation but not more than 50 mg/kg body weightdaily intake.

In another embodiment, when the dosage form is chewed or licked itleaves behind an intense disagreeable color on the tongue, lips andmouth, which requires some cleaning effort to remove, signalling abuseand thus acting as a deterrent.

In a further embodiment, when the dosage form is crushed or grinded andsnorted, inhaled or insuffolated, it leaves behind an intensedisagreeable color on the nose, nasal orifice slips and mouth whichrequires some cleaning effort to remove, signalling abuse and thusacting as a deterrent.

In another embodiment, when the dosage form is crushed or grinded andhandled by hand it leaves behind an intense disagreeable color on thepalm and fingers which requires some cleaning effort to remove,signalling abuse and thus acting as a deterrent.

In another embodiment, when the dosage form is crushed or grinded andplaced in contact with aqueous media it forms a viscous gel with anintense disgusting color impacting negatively on syringability andinjectability and thus acting as a deterrent.

pH Shifting and Release Distortion Formulations/Compositions

In embodiments, following the ingestion of a predetermined amount (suchas the prescribed or recommended amount per dosage regimen) of an intactunit dose form (such as a tablet or capsule), drug release, onset ofaction, and effectiveness is triggered in the presence of gastric fluidup to a pH of about 5. In this case, the amount of the alkalinizingagent present in this predetermined amount is not sufficient toalkalinize or raise the pH of the stomach, for example, from 1-2 or lessthan 4 to a pH between 4 to 13 and the acid labile coating will bepermitted to dissolve, allowing complete release of the activesubstance. However, if more than the predetermined amount of the intactunit dose form is ingested, the combined amount of alkalinizing agent ishigher and will be sufficient to increase the pH of the stomach, forexample, to greater than pH 4 or sufficiently to prevent dissolution ofthe acid labile coating. Therefore, the unit dosage form will remainintact or substantially intact in the stomach indefinitely or for alonger period of time than it otherwise would.

The formulation described herein, requires the presence of gastric fluidthat is of acidic pH (for example, a pH between 1 to 4 and typically, apH less than 2.5), to trigger the release of the active substancethrough dissolution of an acid labile coating. An intact unit dose formon its own contains small amounts of alkalinizing agent(s) (for example,from about 1 mg to about 500 mg depending on the predetermined number ofsolid dosage units to be ingested as per dosage regimen) and that isinsufficient to significantly change the acidic pH of the stomach oningestion. In an embodiment, the predetermined number is 1, 2, 3, 4, or5; in another embodiment, the predetermined number is greater than 6 butless than 20; the predetermined number is greater than 20 but less than100.

These are typically prescribed to be taken intact either once, twice,three times, four times or six times a day. In this acidic environment,the acid labile coat is readily dissolved thus freeing the activecontaining core to disintegrate and release the active substance.However, many unit dose forms (depending on the number of predeterminedunit dosage forms, typically, at least 2 dosage forms) cumulativelycontain more than sufficient amounts of alkalinizing agent(s) to alterstomach pH from an acidic pH to a less acidic pH, neutral pH, or basicpH. In other words, to alter the stomach pH to a pH at which the acidlabile coat will not substantially dissolve over a given period of time.This pH shift results in a basic or less acidic environment (e.g. a pHof from 4 to 12) in which the acid labile coat is not readily dissolved,leaving the unit dose forms intact. This results in the distortion ofdrug release whereby even though more unit dose forms are ingested lessor no active substance is released, contrary to what would be expected.

In other embodiments, following the ingestion of a predetermined amount(such as the prescribed or recommended amount (e.g., 1, 2, 3, 4, or 5tablets or greater than 6 but less than 20 prescribed to be taken intactonce, twice, three times, four times or six times a day) of an intactunit dose form (such as a tablet or capsule), drug release, onset ofaction, and effectiveness is triggered in the presence of intestinalfluid above a pH of about 6. In this case, the amount of the acidifyingagent present in this predetermined amount is not sufficient to acidifythe pH of the duodenum and the base labile coating will be permitted todissolve, allowing complete release of the active substance. However, ifmore than the predetermined amount of the intact unit dose form isingested, the amount of acidifying agent is higher and will besufficient to decrease the pH of the duodenum sufficiently to preventdissolution of the base labile coating. Therefore, the unit dosage formwill remain intact or substantially intact in the duodenum indefinitelyor for a longer period of time than it otherwise would.

The formulation described herein, requires the presence of intestinalfluid that is of basic pH, to trigger the release of the activesubstance through dissolution of a base labile coating. An intact unitdose form on its own contains small amounts of acidifying agent(s) thatis insufficient to significantly change the basic pH of the duodenum oningestion. In this basic environment the base labile coat is readilydissolved thus freeing the active containing core to disintegrate andrelease the active substance. However, many unit dose forms cumulativelycontain more than sufficient amounts of acidifying agent(s) to alterduodenum pH from a basic pH to a less basic pH, neutral pH, or acidicpH. In other words, to alter the duodenum pH to a pH at which the baselabile coat will not substantially dissolve over a given period of time.This pH shift results in an acidic or less basic environment in whichthe base labile coat is not readily dissolved, leaving the unit doseforms intact. This results in the distortion of drug release wherebyeven though more unit dose forms are ingested less or no activesubstance is released, contrary to what would be expected.

The formulations may be directed to a dosage form containing a matrix ornon-matrix core incorporating one or more active ingredients,excipients, and release controlling agent(s).

In the various embodiments described throughout the description, thesurface area concentration of the acid labile substance, such asEudragit E and/or its interpolyelectrolyte complex(es), in the acidlabile coat is at least about 0.5 mg/cm², more typically, at least 4 toabout 10 mg/cm², and even more typically, at least about 10 to about 200mg/cm². For example, the acid labile substance, such as Eudragit Eand/or its interpolyelectrolyte complex(es), may be present in aconcentration of from about 5 mg/cm² to about 100 mg/cm²; typically,about 10 mg/cm² to about 100 mg/cm² and even more typically, about 40mg/cm² to about 100 mg/cm². The amount of acid labile substance, such asEudragit E and/or its interpolyelectrolyte complex(es), in the coat maybe from about 0.2 wt % to about 90 wt % of the dosage form, typically,about 1 wt % to about 80 wt %, or more typically, 2 wt % to about 60 wt%. An amount of the acid labile substance, such as Eudragit E and/or itsinterpolyelectrolyte complex(es), in the coat may be from about 1 mg toabout 500 mg

In the various embodiments described throughout the description, thealkalinizing agent(s) may also be present in the amounts of 0.1 wt % toabout 500 wt % of the composition by weight, typically about 1 wt % toabout 100 wt %, more typically 1 wt % to about 50 wt %. The alkalinizingagent(s) may also be present in an amount of from about 1 mg to about1000 mg The acid labile substance and the alkalinizing agent areselected and used in an amount or proportion depending on the dosingregimen intended such that drug overdose, especially, the overdoseoccurring from ingesting multiple solid oral dosage forms, is prevented,inhibited, or delayed.

In the various embodiments described throughout the description, thesurface area concentration of the base labile substance, such asEudragit L or S and their interpolyelectrolyte complex(es), in the baselabile coat is at least about 0.5 mg/cm², more typically, at least 4 toabout 10 mg/cm², and even more typically, at least about 10 to about 200mg/cm². For example, the base labile substance, such as Eudragit L or S,may be present in a concentration of from about 5 mg/cm² to about 100mg/cm²; typically, about 10 mg/cm² to about 100 mg/cm² and even moretypically, about 40 mg/cm² to about 100 mg/cm². The amount of baselabile substance, such as Eudragit L or S, in the coat may be from about0.2 wt % to about 90 wt % of the dosage form, typically, about 1 wt % toabout 80 wt %, or more typically, 2 wt % to about 60 wt %. These mayalso be present in an amount of from about 1 mg to about 1000 mg. In thevarious embodiments described throughout the description, the acidifyingagent(s) may also be present in the amounts of 0.1 wt % to about 500 wt% of the composition by weight, typically about 1 wt % to about 100 wt%, more typically 1 wt % to about 50 wt %. These may also be present inan amount of from about 1 mg to about 1000 mg.

The base labile substance and the acidifying agent are selected and usedin an amount or proportion depending on the dosing regimen intended suchthat drug overdose, especially, the overdose occurring from ingestingmultiple solid oral dosage forms, is prevented, inhibited, or delayed.These may also be present in an amount of from about 1 mg to about 1000mg.

It will be understood that any pharmaceutically acceptable acid labilesubstance, base labile substance, acidifying agent or alkalinizing agentmay be used in these formulations to achieve the pH shifting and drugrelease distortion phenomenon described.

Formulations Objectionable to Insufflation, Inhaling, Snorting of Milledor Vaporized Powders.

A tussigenic agent may optionally be present in the formulations to makethe compromised formulation objectionable to insufflation, inhalation,or snorting when pulverized, milled, crushed or vapourized. Thetussigenic agent that may be used includes, for example, citric acid,tartaric acid, zinc sulfate, capsaicin, sodium lauryl sulfate, and thelike. With the inclusion of a tussigenic agent in a formulation, whenthe formulation is tampered with, the tussigenic agent imparts adiscomforting quality to the abuser to typically discourage theinsufflation, inhalation, or snorting of the tampered formulation, andtypically to prevent abuse of the formulation.

In the various embodiments described throughout the description, thetussigenic substances may be present in the amounts of 0.0001 wt % toabout 100 wt % of the coat/core by weight, typically about 0.0001 wt %to about 80 wt %, more typically 0.0001 wt % to about 50 wt %. These mayalso be present in an amount of from about 0.0001 mg to about 1000 mg.

An irritant or substance that discourages insufflation may be present inthe formulation. With the inclusion of an irritant (e.g., tobacco,citric acid, quassin, capsaicin and/or sodium lauryl sulfate and/or zincsulfate) in the formulation, when the formulation is tampered with(i.e., pulverized, crushed or milled), the irritant imparts a burning ordiscomforting quality to the abuser to typically discourage theinhalation or snorting of the tampered formulation, and typically toprevent the abuse of the formulation. Suitable capsaicin compositionsinclude capsaicin (trans 8-methyl-N-vanillyl-6-noneamide) or analoguesthereof in a concentration between about 0.00125% and 50% by weight,typically between about 1 and about 7.5% by weight, and most typically,between about 1 and about 5% by weight of the formulation but not morethan 50 mg/kg body weight daily intake. Sodium lauryl sulfate may bepresent in amounts from 0.1% to 200% by weight of the compositions.These may also be present in an amount of from about 0.0001 mg to about1000 mg.

The tussigenic and irritant agents may be used alone or in combination.

The formulation may have one or more of an immediate release, modifiedrelease, delayed release, controlled release or extended release drugcore. The active substance may be any pharmaceutical material that havetherapeutic activity, e.g., without limitation, an opioid agonist, anarcotic analgesic, barbiturates, central nervous system stimulants,tranquilizers, antihypertensive, antidiabetics, and/or antiepileptics.

The formulation can be a solid unit formulation such as, and withoutbeing limited thereto, a tablet, granules, spheres, particles, beads,capsules or microcapsules.

It will be understood that the formulations may not be limited toaddictive substances, and may also be useful in formulations of anyactive ingredient or substance and, indeed, conventional formulationsmay be coated with an acid labile coat and an alkalinizing coat and bewithin the scope described herein.

Administration

The formulation may be administered in-vivo orally, vaginally, anally,ocularly, subcutaneously, intramuscularly, or by implantation. Theformulation may also be used for in vitro or ex vivo delivery of anactive substance. It may be targeted at specific sites in thegastrointestinal tract or to specific organs. It may be appliedoccularly and transdermally in a pouch or patch. It is evident that thephysical state of the formulation and the particular method ofapplication may vary accordingly. Typically, the formulation isadministered orally.

The formulation may reduce the potential for improper administration oruse of drugs but which, when administered as directed, is capable ofdelivering a therapeutically effective dose. In particular, theformulation addresses the need for a drug product, which, compared toconventional formulations, decreases the intensity, quality, frequencyand rate of occurrence of the “euphoria” and other untoward effect,which can occur with improper administration.

In yet another embodiment, the formulation, reduces the potential forimproper administration or use of drugs but which, when administered asdirected, is capable of delivering in a timely fashion, atherapeutically effective dose. In particular, the formulation addressesthe need for a drug product, which, compared to conventionalformulations, decreases the risk of overdose, inhibits, prevents ordelays overdose, reduces the potential for abuse, or decreases the riskof addiction.

In embodiments, the formulation may have a pharmacokinetic profile onsingle dosage administration during fasting and/or feed conditions thatshows a high rate of drug input in the first hour which is at least 5times the rate of drug input at subsequent hourly intervals.

In another embodiment, the formulation is a 40 mg oxycodonehydrochloride tablet wherein the pharmacokinetic profile on single doseadministration shows a mean plasma concentration per unit of time ofbetween about 15 ng/ml and about 35 ng/ml between about the first hourand about the sixth hour.

Various Formulations

In one embodiment, the formulation comprises: one or more of a modifiedrelease, delayed release, controlled release and/or extended releasecore containing an active substance; surrounded first by one or morelayers of an acid labile coat; followed by one or more layers of analkalinizing coat.

In certain embodiments, the formulation may include a dose of an activesubstance within the core and a further dose of the same or a differentactive substance outside of the core to provide a loading dose. Theloading dose may be incorporated within the acid labile or alkalinizingcoat or it may exist in its own coating layer external to thealkalinizing coat, internal to the acid labile coat, or in between thealkalinizing coat and the acid labile coat.

In another embodiment, the formulation comprises: one or more of amodified release, delayed release, controlled release and/or extendedrelease core containing an active substance; surrounded first by one ormore layers of a base labile coat; followed by one or more layers of anacidifying coat, and further followed by one or more layers of a baselabile coat.

In certain embodiments, the formulation may include a dose of an activesubstance within the core and a further dose of the same or a differentactive substance outside of the core to provide a loading dose. Theloading dose may be incorporated within one or more of the base labileor acidifying coat or it may exist in its own coating layer external tothe acidifying coat, internal to the base labile coat, or in between theacidifying coat and the base labile coat.

The formulation may contain one or more different active substances.

In the various formulations, the active substance is released in one ormore time intervals.

The formulation may comprise one or more active substance(s) in apharmaceutically effective amount, wherein the formulation has isconfigured such that when the formulation is administered in unit dosageforms, the rate and/or amount of active substance(s) released from thecomposition is inversely proportional to the number of unit dosage formsadministered. For example, administration of 2 or more, 3 or more, 4 ormore, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, or 10 ormore unit dosage forms will inhibit, delay, or prevent release of theactive substance as compared to administration of a single unit dosageform or a number that is lower than that which was actually intended tobe administered under normal circumstances. The delay of release of theactive substance may be by a time period selected from the groupconsisting of about 0.5 hours, about 1 hour, about 2 hours, about 3hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about8 hours, about 9 hours, or about 10 hours. The inhibition of release ofthe active substance may be by an amount of about 10% or more, 20% ormore, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more,80% or more, 90% or more, 95% or more, or 99% or more. Thus, if apatient were prescribed one unit dosage form and ingested, for example,3 or 4 or more either on purpose or accidentally, release of the activesubstance would be inhibited, delayed, or prevented. In this way, moretime is available for the patient to seek medical intervention in orderto avoid or mitigate the effects of an overdose. In typical embodiments,the amount of active substance(s) in the formulation is from about 0.1mg to about 1000 mg, and any ranges or amounts therebetween.

The formulation may comprise one or more active substance(s) (e.g. fromabout 1 mg to about 1000 mg of Oxycodone, Hydrocodone, Oxymorphone,Hydromorphone, Morphine, Codeine or combinations of these with fromabout 1 mg to about 1000 mg of NSAIDs such as Acetaminophen, Ibuprofin,Aspirin, Naproxen sodium or Meloxicam) in a pharmaceutically effectiveamount, wherein the formulation has a acid labile coat and aalkalinizing coat and optionally acidifying coat and is configured suchthat when the formulation is administered in unit dosage forms, the rateand/or amount of active substance(s) released from the composition isinversely proportional to the number of unit dosage forms administered.For example, administration of 2 or more, 3 or more, 4 or more, 5 ormore, 6 or more, 7 or more, 8 or more, 9 or more, or 10 or more unitdosage forms intact and at once will lead to change in stomach pH fromacid (of pH1 to pH 3) to less acidic to basic (of between pH 4 to pH12). This change in pH will inhibit, delay, or prevent release of theactive substance as compared to administration of a single unit dosageform or a number that is lower than that which was actually intended tobe administered under normal circumstances. The delay of release of theactive substance may be by a time period selected from the groupconsisting of about 0.5 hours, about 1 hour, about 2 hours, about 3hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about8 hours, about 9 hours, or about 10 hours. The inhibition of release ofthe active substance may be by an amount of about 10% or more, 20% ormore, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more,80% or more, 90% or more, 95% or more, or 99% or more in a 24 hourperiod. Thus, if a patient were prescribed one unit dosage form andingested, for example, 3 or 4 or more either on purpose or accidentally,release of the active substance would be inhibited, delayed, orprevented. In this way, more time is available for the patient to seekmedical intervention in order to avoid or mitigate the effects of anoverdose.

The formulation may comprise one or more active substance(s) (e.g. fromabout 1 mg to about 1000 mg of Oxycodone, Hydrocodone, Oxymorphone,Hydromorphone, Morphine, Codeine or combinations of these with fromabout 1 mg to about 1000 mg of NSAIDs such as Acetaminophen, Ibuprofin,Aspirin, Naproxen sodium or Meloxicam) in a pharmaceutically effectiveamount, wherein when the formulation is administered in a higher thanprescribed dose to a subject, the rate of active substance(s) releasedfrom the composition, within a time period selected from the groupconsisting of about 0.5 hours, about 1 hour, about 2 hours, about 3hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about8 hours, about 9 hours, or about 10 hours, is substantially the same orlower, typically less than 20%, more typically less than 30%, and mosttypically less than 40%, than the amount of active substance(s) releasedwhen the pharmaceutical composition is administered in the prescribeddose.

The formulation may comprise one or more active substance(s) (e.g. fromabout 1 mg to about 1000 mg of Oxycodone, Hydrocodone, Oxymorphone,Hydromorphone, Morphine, Codeine or combinations of these with fromabout 1 mg to about 1000 mg of NSAIDs such as Acetaminophen, Ibuprofin,Aspirin, Naproxen sodium or Meloxicam) in a pharmaceutically effectiveamount, wherein the formulation is configured such that when theformulation is administered in a prescribed dose, at least 50% of theamount of active substance(s) is released after about 8 hours and whenthe formulation is administered in a higher than prescribed dose at mostabout 55%, typically at most about 50%, more typically at most about30%, of the amount of active substance(s) is released in about 1 hour.

The formulation may comprise one or more active substance(s) (e.g. fromabout 1 mg to about 1000 mg of Oxycodone, Hydrocodone, Oxymorphone,Hydromorphone, Morphine, Codeine or combinations of these with fromabout 1 mg to about 1000 mg of NSAIDs such as Acetaminophen, Ibuprofin,Aspirin, Naproxen sodium or Meloxicam in a pharmaceutically effectiveamount, wherein the formulation is configured such that when theformulation is administered in a prescribed dose, at least 80% of theamount of active substance(s) is released after about 1 hour and whenthe formulation is administered in a higher than prescribed dose at mostabout 70% of the amount of active substance(s) is released in about 1hour.

In yet another embodiment, the formulation is designed such that in thetreatment of severe to moderate pain using opioid analgesics (e.g. fromabout 1 mg to about 1000 mg of Oxycodone, Hydrocodone, Oxymorphone,Hydromorphone, Morphine, Codeine or combinations of these with about 1mg to about 1000 mg of NSAIDs such as Acetaminophen, Ibuprofin, Aspirin,Naproxen sodium or Meloxicam) timely delivery of onset of pain reliefand adequate pain relief is experienced by the patient from about 30,about 60, about 120, about 180 or about 240 minutes. In anotherembodiment, the formulation is designed such that the formulation orcomposition can be administered every 8 hours to 12 hours to every 24hours.

In certain formulations, the active substance(s) and/or inactivesubstance(s) used in the formulation have a fine, small or low particlesize and large, high or big surface area. Accordingly, the particle sizeis less than 1500 microns, typically less than 1000 microns and moretypically less than 400 microns.

In certain formulations, a loading dose is applied as a coat around thecore or around the acid labile coat, the base labile coat, theacidifying coat or the alkalinizing coat of the formulation orcomposition.

In certain formulations, such as from about 1 mg to about 1000 mg ofOxycodone, Hydrocodone, Oxymorphone, Hydromorphone, Morphine, Codeine orcombinations of these with about 1 mg to about 1000 mg of NSAIDs such asAcetaminophen, Ibuprofin, Aspirin, Naproxen sodium or Meloxicam, aloading dose is applied as a coat around the core or around the acidlabile coat, the base labile coat, the acidifying coat or thealkalinizing coat of the formulation or composition.

The formulation may have one or more of an immediate release, modifiedrelease, delayed release, controlled release or extended release drugcore; optionally surrounded first by one or more layers of drug embeddedin a non-functional coat followed by an acid labile coat then analkalinizing coat or a base labile coat then an acidifying coat, andfurther another base labile coat. The active substance may be, withoutlimitation, an opioid agonist, a narcotic analgesic, a barbiturate, acentral nervous system stimulant, a tranquilizer, an antihypertensive,an antidiabetic, and/or an antiepileptic. Prior to incorporation withinthe core or coat, the active substance may be in any suitable form knownin the art, such as liquid, semi-solid, solid, paste, or gel, and may behomogenously or non-homogenously dispersed in the core.

The formulation can be a solid unit formulation such as, and withoutbeing limited thereto, a tablet, granules, spheres, particles, beads,capsules, or microcapsules.

It will be understood that the formulations may not be limited toaddictive substances, and may also be useful in formulations of anyactive ingredient or substance. Additionally, any known conventionalunit dosage form may be coated with an acid labile coat and analkalinizing coat in order to prevent, reduce, inhibit, and/or slow theonset of an overdose. Likewise, any known conventional unit dosage formmay be coated with a base labile coat, then an acidifying coat, followedby another base labile coat, in order to prevent, reduce, inhibit,and/or slow the onset of an overdose. It will be understood that if theconventional unit dosage form is, for example, an enteric coated dosageform then an acidifying coat followed by a base labile coat issufficient.

Several embodiments of the formulations are provided:

Formulations herein may also comprise at least one active substance thathas an analgesic ceiling effect and/or no ceiling effect.

In an embodiment, there is provided a formulation that is effectivelyemployed to control the release of one or more active substances orprevent the instantaneous release of the entire dose in the formulationwhen a dose above a threshold dose (e.g., a prescribed dose) isingested.

The formulation may have a modified release, delayed release, controlledrelease or extended release formulation and in which the physicochemicalnature of the formulation is used to reduce the potential andconsequences (drug overdose, addiction, suboptimal efficacy, and/ordeath) of improper administration of medications and their use in anon-indicated or non-prescribed manner.

An immediate release, delayed release, modified release, extendedrelease, pulsed release, sustained release or controlled release profileprovided by the formulations disclosed herein may advantageously be usedin the formulation of any active ingredient.

A formulation may comprise a core with one or more of a releaseretarding agent, a controlled release agent, a gelling agent, apolymeric agent, and one or more fillers in a pharmaceutically suitablevehicle, and optionally materials selected from disintegrants,compression aids, lubricants, humectants, surfactants, emulsifiers,plasticizers, antioxidants, and stabilizers.

A formulation may be formulated such that its physicochemical propertiesdiscourage drug abuse by ingesting multiple unit dosage forms in amountsthat would be generally higher than prescribed or would generally beconsidered harmful or potentially harmful. The formulation may also beformulated such that its physicochemical properties discourage abuse bymodes of crushing, milling or grinding the formulation to powder orheating the formulation to vapor and snorting or inhalation by the nasalroute or dissolving to abuse via the parenteral route.

A formulation may comprise a core surrounded by an acid labile coat, analkalinizing coat, and a polymeric coat, a plastic coat or elastic coatand the like. Alternatively, a formulation may comprise a coresurrounded by a base labile coat, an acidifying coat, a further baselabile coat, and a polymeric coat, a plastic coat or elastic coat andthe like.

Where a formulation of the present invention comprises more than onecoat, a first coat substantially surrounds or envelops a core, a secondcoat substantially surrounds or envelopes the first coat, and so forth.Typically, an acid labile coat is closer to the core than analkalinizing coat, as the acid labile coat protects the core fromdisintegrating in non-acidic environments. Likewise, typically, at leastone of the base labile coats is closer to the core than an acidifyingcoat, as the base labile coat protects the core from disintegrating innon-basic environments.

Coats may take the form and composition of any known compatiblecontrolled-release coat, for example a pH sensitive coat, ion-exchangeresin coat (containing, for example, cholestyramine, colestipol, sodiumpolystyrene sulfonate, polacrilex resin, or polacrilin potassium),intestinal bacteria flora or enzyme reactive polymer (such as apolysaccharide-based coat), a water repellant coat, an aqueoussolvent-based coat, or a water-soluble coat. The formulations may havean overcoat. Typically, such coats comprise at least one or more polymercomposition such as, but not limited to, Opadry and the like.Alternatively, Opadry or the like may be included in the alkalinizingcoat as desired.

In embodiments, the acid labile coat or base labile coat thickness isbelow 1000 mg/cm², typically below 200 mg/cm² and more typically below100 mg/cm². In aspects, the acid labile coat thickness is from about 1mg/cm² to about 100 mg/cm², such as from about 10 mg/cm² to about 100mg/cm², from about 8 to about 50 mg/cm², from about 8 to about 12mg/cm², about 15 to about 20 mg/cm², about 19 to about 25 mg/cm², about25 to about 35 mg/cm², about 30 to about 40 mg/cm², or about 40 to about50 mg/cm². In an aspect, said at least one base labile coat is presentin an amount of from about 0.5 to about 50 mg/cm² or from about 8 toabout 50 mg/cm² or from about 0.5 to about 8 mg/cm².

The alkalinizing coat or acidifying coat typically has a thickness offrom about 2 mg/cm² to about 100 mg/cm², or 15 mg/cm² to about 55mg/cm², or 10 mg/cm² to about 40 mg/cm², or 40 mg/cm² to about 80mg/cm², or 80 mg/cm² to about 100 mg/cm².

In embodiments, the coating is applied to cause about 1% to about 200%weight gain, about 2.5% to about 150% weight gain, such as from about2.5% to about 100%, or from about 3% to about 80% weight gain.

In aspects, the alkalinizing coat is applied to cause from about 1% toabout 200% weight gain, such as from about 5% to about 80%, from about1% to about 70% weight gain, from about 1% to about 50% or from about 5%to about 50% weight gain.

In aspects, the base labile coat is applied to cause from about 1% toabout 200% weight gain, such as from about 1% to about 70% or from about1% to about 50% weight gain.

In aspects, the acidifying coat is applied to cause from about 1% toabout 200% weight gain, such as from about 1% to about 70% or from about1% to about 50% weight gain.

In aspects, the acid labile coat is applied to cause from about 1% toabout 200% weight gain, such as from about 1% to about 70% or from about1% to about 50% weight gain.

In embodiments, the alkalinizing coat is present in an amount sufficientto raise the pH of the stomach, such that dissolution of at least oneacid labile coat and release of the active substance is inhibited whenthe number of unit dosage forms ingested exceeds a predetermined number.In a specific embodiment, the alkalinizing coat comprises at least about1 mg alkalinizing agent(s) in the unit dosage form/formulation butpresent in an amount sufficient to raise the pH of an acid media or thestomach to greater than about pH 2, such that dissolution of the acidlabile coat and release of the active substance is inhibited when thenumber of unit dosage forms ingested (or is present in an acid media)exceeds a predetermined number.

The alkalinizing coat may have at least one alkalinizing agent in anamount of at least about 1 mg per unit dosage form but such that whenmore tablets or dosage forms than prescribed are swallowed at once thepH of the stomach changes to alkaline. In an embodiment, thealkalinizing coat has at least one alkalinizing agent in an amount of atleast about 1 mg per tablet or unit dosage form but such that when about1 to about 100 dosage forms are present at once in an acid media of pHless than about 5, the pH changes to alkaline. In another embodiment,the alkalinizing coat has at least one alkalinizing agent in an amountof at least about 1 mg per tablet or unit dosage form but such that whenup to 100 dosage forms, or up to 20 dosage forms, or more than 1, 2, 3,4, 5, or 6 of dosage forms are present at once in an acid media of pHless than about 4, the pH changes to pH greater than about 4 andtypically, greater than about 6.

In embodiments, the acidifying coat is present in an amount sufficientto lower the pH of the duodenum such that dissolution of the at leastone base labile substance and release of the at least one activesubstance is inhibited when the number of unit dosage forms ingestedexceeds a predetermined number. In a specific embodiment, the acidifyingcoat comprises at least about 1 mg acidifying agent(s) in the unitdosage form/formulation but present in an amount sufficient to lower thepH of a basic media or the duodenum to less than about pH of 4, andtypically, to a pH less than 2, such that dissolution of the base labilecoat and release of the active substance is inhibited when the number ofunit dosage forms ingested (or is present in an acid media) exceeds apredetermined number.

In embodiments, the base labile coat comprises at least about 1 mg ofbase labile substance per tablet or unit dosage form. In embodiments,the acid labile coat comprises at least about 1 mg of acid labilesubstance per tablet or unit dosage form.

The formulations described herein may release up to about 55% of thetotal dose as a loading dose to manage pain. In certain embodiments, upto about 55% of the total dose is released as a loading dose withinabout 60 minutes of ingestion.

For formulations targeted for pain management, such as those selectedfrom the group comprising from about 1 mg to about 1000 mg of Oxycodone,Hydrocodone, Oxymorphone, Hydromorphone, Morphine, Codeine orcombinations of these with from about 1 mg to about 1000 mg of NSAIDssuch as Acetaminophen, Ibuprofin, Aspirin, Naproxen sodium or Meloxicam,the total dose released as a loading dose within about 60 minutes toabout 120 minutes of ingestion, may be from about 1 mg to about 1000 mgof the active pharmaceutical ingredient(s).

The release profile of the formulation depending upon the number of unitdosage forms ingested may be modified on the basis of many factorspertaining to the formulation, particle size and surface area of theactive pharmaceutical ingredient and polymers used, design of thephysical geometry of the formulation polymeric coats, for example,without limitation, through the choice of particle size and surfacearea, types of polymers, acid or base labile coats, and alkalinizing oracidifying agents used, the presence or absence of a loading dose, theorder in which they are deposited, the ratios of the loading dose tomaintenance dose, the ratios of the polymers in the mix and the natureof their interaction. The controlled-release profile can also bemodified by a variety of factors relating to the delivery formulationand the route of administration. For example, the sustained-releaseperiod and profile will vary depending upon the alkalinizing oracidifying agent concentration, solubility of the acid or base labilecoating and the active ingredient, the rate of clearance of the activeingredient from the intended site of administration, the size andsurface area of the particle, the amount of the active ingredientinitially present in the core, the presence of other compounds withinthe core that affect the rate of release of the active ingredient, thepermeability of the coating(s) to the active pharmaceutical ingredient,and the rate of degradation of the coating(s), as well as other factors.

Release control may be effected or optimized through the types of acidor base labile agents and alkalinizing or acidifying agents used, thenumber of coats, the order in which they are deposited, the width ofcoats and surface area covered, the ratios of the components in the mixand the nature of their interaction.

Incorporating an active substance as described, in the formulationherein, may be useful for (1) reducing the risk of accidental orintentional overdose, (2) increasing the amount of time required for anoverdose to occur, thereby increasing the likelihood of a suitabletimely intervention, (3) reducing abuse potential of addictivesubstances, (4) reducing the chance or opportunity for a patient tomistakenly or purposely ingest a higher dose of an addictive activesubstance and become addicted, and (5) reducing at least one mode ofabuse, for example, the illicit use by snorting/inhalation, parenteraladministration, or crushing and oral ingestion of formulations intendedfor oral administration.

The formulations may comprise additives such as polyethylene oxidepolymers, polyethylene glycol polymers, cellulose ether polymers,cellulose ester polymers, homo- and copolymers of acrylic acidcross-linked with a polyalkenyl polyether, poly(meth)acrylates,homopolyers (e.g., polymers of acrylic acid crosslinked with allylsucrose or allyl pentaerythritol), copolymers (e.g., polymers of acrylicacid and C10-C30 alkyl acrylate crosslinked with allyl pentaerythritol),interpolymers (e.g., a homopolymer or copolymer that contains a blockcopolymer of polyethylene glycol and a long chain alkyl acid ester),disintegrants, ion exchange resins, polymers reactive to intestinalbacterial flora (e.g., polysaccharides such as guar gum, inulin obtainedfrom plant or chitosan and chondrotin sulphate obtained from animals oralginates from algae or dextran from microbial origin) andpharmaceutical resins.

In some formulations, the core and/or the coat may contain ingredientsthat, when combined with an aqueous solution, will agglomerate toprevent abuse. Such combinations of ingredients include swellablematerials such as PEO and Eudragit RL (or other non-enteric compounds).In general, a formulation may comprise at least one active substance;and at least one excipient, wherein dissolution of the pulverized/milledformulation in alcoholic and/or non-alcoholic beverages causes theformulation to agglomerate.

In some formulations, the core and/or one or more coat may contain adisintegrant in an amount of from about 0% to 99% by weight, typicallyfrom about 1% to 90% by weight and more typically from 2% to 85%.

Any one of these materials may be present in the formulation orcomposition in about from 0% to 99% by weight, typically from about 1%to 90% by weight and more typically from 5% to 85%.

The formulations may optionally comprise a pharmaceutically acceptablenasal irritant such as capsicum oleoresin. A nasal irritant can producenasal irritation and a feeling of annoyance when the composition isbrought in contact with the nasal membrane. The irritant agent isgenerally not in amounts sufficient to precipitate allergic typereactions or immune response upon snorting. U.S. Pat. No. 7,157,103suggests the use of various irritants in preparing pharmaceuticalformulations including, for example, capsaicin, a capsaicin analog withsimilar type properties as capsaicin, and the like. Some capsaicinanalogues or derivatives include for example, resiniferatoxin,tinyatoxin, heptanoylisobutylamide, heptanoyl guaiacylamide, otherisobutylamides or guaiacylamides, dihydrocapsaicin, homovanillyloctylester, nonanoyl vanillylainide, or other compounds of the classknown as vanilloids. Resiniferatoxin is described, for example, in U.S.Pat. Nos. 5,290,816, and 4,812,446 describes capsaicin analogs andmethods for their preparation.

Some examples of controlled release agents that may be used in theformulation of the invention include naturally occurring or synthetic,anionic or nonionic, hydrophobic, hydrophilic rubbers, polymers, starchderivatives, cellulose derivatives, polysaccharides, carbomer, reseins,acrylics, proteins, vinyl-pyrrolidone-vinyl-acetate-copolymers,galactomannan and galactomannan derivatives, carrageenans and the like.Specific examples are acacia, tragacanth, Xanthan gum, locust bean gum,guar-gum, karaya gum, pectin, arginic acid, polyethylene oxide,polyethylene glycol, propylene glycol arginate, hydroxypropylmethylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose, carboxymethylcellulose sodium, polyvinylpyrrolidone,carboxyvinyl polymer, sodium polyacrylate, a starch, sodiumcarboxymethyl starch, albumin, dextrin, dextran sulfate, agar, gelatin,casein, sodium casein, pullulan, polyvinyl alcohol, deacetylatedchitosan, polyethyoxazoline, poloxamers, ethylcellulose, chitin,chitosan, cellulose esters, aminoalkyl methacrylate polymer, anionicpolymers of methacrylic acid and methacrylates, copolymers of acrylateand methacrylates with quaternary ammonium groups, ethylacrylatemethylmethacrylate copolymers with a neutral ester group,polymethacrylates, surfactants, aliphatic polyesters, zein, polyvinylacetate, polyvinyl chloride, and the like. Further examples ofpharmaceutically acceptable acrylic polymers that may also be usedinclude, but are not limited to, acrylic acid and methacrylic acidcopolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates,cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylicacid), poly(methacrylic acid), methacrylic acid alkylamide copolymer,poly(methyl methacrylate), poly(methyl methacrylate) copolymer,polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acidanhydride), and glycidyl methacrylate copolymers. Additionally, theacrylic polymers may be cationic, anionic, or non-ionic polymers and maybe acrylates, methacrylates, formed of methacrylic acid or methacrylicacid esters. The polymers may also be pH independent or pH dependent.

Further examples of additives that may be used in the formulation of theinvention include, but are not limited to, ethyl lactate, phthalatessuch as dimethyl phthalate (DMP), diethyl phthalate (DEP), dibutylphthalate (DBP), dioctyl phthalate, glycol ethers such as ethyleneglycol diethyl ether, propylene glycol monomethyl ether, PPG-2 myristylether propionate, ethylene glycol monoethyl ether, diethylene glycolmonoethyl ether, propylene glycol monotertiary butyl ether, dipropyleneglycol monomethyl ether, N-methyl-2-pyrrolidone, 2 pyrrolidone,isopropyl myristate, isopropyl palmitate, octyl palmitate,dimethylacetamide, propylene glycol, propylene glycol monocaprylate,propylene glycol caprylate/caprate, propylene glycol monolaurate,glycofurol, linoleic acid, linoeoyl macrogol-6 glycerides, oleic acid,oleic acid esters such as glyceryl dioleate, ethyl oleate, benzoic acid,oleoyl macrogol-6 glycerides, esters such as ethylbenzoate,benzylbenzoate, sucrose esters, sucrose acetate isobutyrate, esters oflactic acid, esters of oleic acid, sebacates such as dimethyl sebacate,diethyl sebacate, dibutyl sebacate, dipropylene glycol methyl etheracetate (DPM acetate), propylene carbonate, propylene glycol laurate,propylene glycol caprylate/caprate, gamma butyrolactone, medium chainfatty acid triglycerides, glycerol and PEG esters of acids and fattyacids, PEG-6 glycerol mono oleate, PEG-6 glycerol linoleate, PEG-8glycerol linoleate, caprylic acid esters such as caprylocaprylmacrogol-8 glycerides, PEG-4 glyceryl caprylate/caprate, PEG-8 glycerylcaprylate/caprate, polyglyceryl-3-oleate, polyglyceryl-6-dioleate,polyglyceryl-3-isostearate, polyglyceryl polyoleate, decaglyceryltetraoleate and glyceryl triacetate, glyceryl monooleate, glycerylmonolinoleate, dimethylformamide, dimethylsulfoxide, tetrahydrofuran,caprolactam, decylmethylsulfoxide, and 1-dodecylazacycloheptan-2-one.

The formulation may also contain self-emulsifying or surface activesubstances with varying hydrophilic lipophilic balance (HLB) values suchas polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil,polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkylesters, polyoxyethylene alkyl ethers, polyoxyethylene glycerol esters,sorbitan fatty acid esters, and sodium lauryl sulphate.

Examples of antioxidants that may be used in the formulation is selectedfrom ascorbic acid, fumaric acid, malic acid, a tocopherol, ascorbicacid palmitate, butylated hydroxyanisole, propyl gallate, sodiumascobate, and sodium metabisulfite or other suitable antioxidants andstabilizers.

Examples of plasticizers that may be used in the formulation includeadipate, azelate, enzoate, citrate, stearate, isoebucate, sebacate,triethyl citrate, tri-n-butyl citrate, acetyl tri-n-butyl citrate,citric acid esters, and those described in the Encyclopedia of PolymerScience and Technology, Vol. 10 (1969), published by John Wiley & Sons.The typical plasticizers are triacetin, acetylated monoglyceride,acetyltributylcitrate, acetyltriethylcitrate, glycerin sorbitol,diethyloxalate, diethylmalate, diethylphthalate, diethylfumarate,dibutylsuccinate, diethylmalonate, dioctylphthalate, dibutylsebacate,triethylcitrate, tributylcitrate, glyceroltributyrate, polyethyleneglycol, glycerol, vegetable and mineral oils and the like. Depending onthe particular plasticizer, amounts of from 0 to about 25%, andtypically about 0.1% to about 20% of the plasticizer can be used. Theaddition of plasticizer should be approached with caution. In certaincompositions it is better not to use plasticizers.

Examples of other additives that may be used as part of the formulationsof the invention include, but are not limited to disintegrants,carbohydrates, sugars, sucrose, sorbitol, mannitol, zinc salts, tannicacid salts; salts of acids and bases such as sodium and potassiumphosphates, sodium and potassium hydroxide, sodium and potassiumcarbonates and bicarbonates; acids such as hydrochloric acid, sulfuricacid, nitric acid, lactic acid, phosphoric acid, citric acid, malicacid, fumaric acid, stearic acid, tartaric acid, boric acid, borax, andbenzoic acid.

Examples of disintegrants include: alginic acid, carboxymethylcellulosecalcium, carboxymethylcellulose sodium, colloidal silicon dioxide,croscarmellose sodium, crospovidone, guar gum, magnesium aluminumsilicate, methylcellulose, microcrystalline cellulose, polyacrilinpotassium, powdered cellulose, pregelatinized starch, sodium alginateand starch.

Organic acid(s) may particularly be used, for example, lactic acid,phosphoric acid, citric acid, malic acid, fumaric acid, stearic acid,tartaric acid, and benzoic acid. Such acids modify the pH of the macroand micro environment to facilitate release of the active substance. Theacid(s) may be included in the coat(s), including the overcoat,layer(s), and/or core of the formulation.

Materials such as the alkali metal chlorides, ammonium chloride, andchlorides of Ba, Mg, Ca, Cu, Fe and Al; alkali or alkaline earthsolutions of acetates, nitrates, phosphates, and hydroxides may be usedin this formulation Hygroscopic or aqueous materials may be used butwith caution. Limited quantities may be incorporated in certaincompositions.

Water insoluble organosoluble polymers may be used in the formulation,which may be any polymers which are insoluble in water, are capable ofbeing homogenously dissolved or dispersed in an organosolvent, and cantypically retard the release of active ingredients. By the term“water-insoluble” is intended not susceptible to being dissolved (inwater). Specific examples of water insoluble organosoluble polymers are,cellulose ether, cellulose ester, or cellulose ether-ester e.g., ethylcellulose, acetyl cellulose, and nitrocellulose. Other water insolubleorganosoluble polymers that can be used include acrylic and/ormethacrylic ester polymers, polymers or copolymers of acrylate ormethacrylate polyvinyl esters, polyvinyl acetates, polyacrylic acidesters, and butadiene styrene copolymers, and the like. Typical waterinsoluble polymers are ethylcellulose, cellulose acetate,polymethacrylates and aminoalkyl methacrylate copolymer.

In further specific examples, the acrylic polymer, includes, but is notlimited to, acrylic acid and methacrylic acid copolymers, methylmethacrylate copolymers, ethoxyethyl methacrylates, cyanoethylmethacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid),poly(methacrylic acid), methacrylic acid alkylamide copolymer,poly(methyl methacrylate), poly(methyl methacrylate) copolymer,polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acidanhydride), and glycidyl methacrylate copolymers. Additionally, theacrylic polymers may be cationic, anionic, or non-ionic polymers and maybe acrylates, methacrylates, formed of methacrylic acid or methacrylicacid esters. The water insoluble polymers can be used either singly orin combinations of two or more.

Water-soluble gel forming polymers, which may be used in theformulation, may be any polymers, which are soluble in water, arecapable of being homogenously dissolved or dispersed in anorganosolvent, and can typically retard the release of activeingredients. Typically, the water-soluble gel-forming polymer is capableof hydrating quickly and forming strong, viscous gels. By the term“water-soluble” is intended susceptible of being dissolved (in water).Suitable water-soluble gel forming polymers include those which can formhydrocolloid or can form a strong, viscous gel through which an activeingredient is released via diffusion or wicking or erosion or swelling.They include naturally occurring or synthetic, anionic or nonionic,polyethylene oxide, hydrophilic rubbers, starch derivatives, cellulosederivatives, proteins, and the like. Specific non-limiting examples arepolyethylene oxide and or its derivatives, gelatin, such as alginates,pectins, carrageenans, or xanthan; cellulose derivatives, such as methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, or sodium carboxymethylcellulose; starch and starchderivatives such as a starch or sodium carboxymethyl starch;galactomannan and galactomannan derivatives; polyvinylpyrrolidone,polyvinyl alcohol, polyvinyl acetate and the like,vinyl-pyrrolidone-vinyl-acetate-copolymers, acacia, tragacanth, xanthangum, locust bean gum, guar-gum, karaya gum, pectin, arginic acid,polyethylene oxide, Carbomer, polyethylene glycols, polypropyleneglycols, carboxyvinyl polymer, sodium polyacrylate, albumin, dextrin,dextran sulfate, agar, gelatin, casein, sodium casein, pullulan,deacetylated chitosan, polyethyoxazoline, polyethylene oxide, poloxamersand the like. Of these, typical ones are polyethylene oxide,hydroxyethyl cellulose, hydroxypropyl methylcellulose, methylcellulose,hydroxypropyl cellulose, carbomer, polyethylene glycol, poloxamers,starch derivatives and polyvinylpyrrolidone. Water-soluble gel formingpolymers can be used either singly or in combinations of two or more.

Polymeric coats may also be comprised of: hydrophobic or water repellantmaterial such as oils, fats, waxes, higher alcohols; pH sensitivepolymers; enteric polymers; or any other polymer, component or materialknown to be useful for preparing a controlled release coating. Thepolymers used in the formulation may be pH insensitive or pH sensitive.

For a delivery formulation designed to be orally administered to thedigestive tract, polymers that are known to be orally ingestible can beused and include, for example, polyvinyl alcohol, hydroxypropyl methylcellulose, and other cellulose-based polymers. Other known polymersuseful for enteral delivery include polymer materials, whichpreferentially dissolve or disintegrate at different points in thedigestive tract. Such polymers include, for example, the known acrylicand/or methacrylic acid-based polymers, which are soluble in intestinalfluids, e.g. the Eudragit™ series of commercially available polymers.Examples of these include Eudragit E™, such as Eudragit E100™ whichpreferentially dissolves in the more acid pH of the stomach, or entericpolymers such as Eudragit L™ and/or Eudragit S™ which preferentiallydissolve in the more alkaline pH of the intestine, or polymers whichdissolve slowly, e.g. a predetermined rate in the digestive tract, suchas Eudragit RL™, e.g. Eudragit RL100™, and/or Eudragit RS™ e.g. EudragitR100™, and/or blends of such Eudragit™ polymers.

Polymeric coats may also be comprised of: ion exchange resins and orpolymers reactive to intestinal bacterial flora (e.g., polysaccharidessuch as guar gum, inulin obtained from plant or chitosan and chondrotinsulphate obtained from animals or alginates from algae or dextran frommicrobial origin)

Hydrophobic or water repellant material that may be present is chosenfrom oil and fats, waxes, higher fatty acids, fatty acid esters, higheralcohols, hydrocarbons, and metal salts of higher fatty acids. Specificexamples of oils and fats include plant oils, e.g. cacao butter, palmoil, Japan wax (wood wax), coconut oil, etc.; animal oils, e.g. beeftallow, lard, horse fat, mutton tallow, etc.; hydrogenated oils ofanimal origin, e.g. hydrogenated fish oil, hydrogenated whale oil,hydrogenated beef tallow, etc.; hydrogenated oils of plant origin, e.g.hydrogenated rape seed oil, hydrogenated castor oil, hydrogenatedcoconut oil, hydrogenated soybean oil, etc.; and the like. Of thesehydrogenated oils are typical as an oil component of the presentinvention.

Specific examples of waxes that may be present include plant waxes, e.g.carnauba wax, candelilla wax, bayberry wax, auricurry wax, espalt wax,etc.; animal waxes, e.g. bees wax, breached bees wax, insect wax,spermaceti, shellac, lanolin, etc; and the like. Of these typical onesare carnauba wax, white beeswax and yellow beeswax.

Paraffin, petrolatum, microcrystalline wax, and the like, are given asspecific examples of hydrocarbons, with typical hydrocarbons beingparaffin and microcrystalline wax.

Given as examples of higher fatty acids are caprilic acid, undecanoicacid, lauric acid, tridecanic acid, myristic acid, pentadecanoic acid,palmitic acid, malgaric acid, stearic acid, nonadecanic acid, arachicacid, heneicosanic acid, behenic acid, tricosanic acid, lignoceric acid,pentacosanic acid, cerotic acid, heptacosanic acid, montanic acid,nonacosanic acid, melissic acid, hentriacontanic acid, dotriacontanicacid, and the like. Of these, preferable are myristic acid, palmiticacid, stearic acid, and behenic acid.

Specific examples of higher alcohols are lauryl alcohol, tridecylalcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, heptadecylalcohol, stearyl alcohol, nonadecyl alcohol, arachyl alcohol, behenylalcohol, carnaubic alcohol, corianyl alcohol, ceryl alcohol, and myricylalcohol. Particularly preferable alcohols are cetyl alcohol, stearylalcohol, and the like.

Specific examples of esters are fatty acid esters, e.g. myristylpalmitate, stearyl stearate, myristyl myristate, behenyl behenate, ceryllignocerate, lacceryl cerotate, lacceryl laccerate, etc.; glycerinefatty acid esters, e.g. lauric monoglyceride, myristic monoglyceride,stearic monoglyceride, behenic monoglyceride, oleic monoglyceride, oleicstearic diglyceride, lauric diglyceride, myristic diglyceride, stearicdiglyceride, lauric triglyceride, myristic triglyceride, stearictriglyceride, acetylstearic glyceride, hydoxystearic triglyceride, etc.;and the like. Glycerine fatty acid esters are more typical.

Specific examples of metal salts of higher fatty acid are calciumstearate, magnesium stearate, aluminum stearate, zinc stearate, zincpalmitate, zinc myristate, magnesium myristate, and the like, withpreferable higher fatty acid salts being calcium stearate and magnesiumstearate.

A coating composition may also contain other additives such asdisintegrants and additives normally found in coatings used in thepharmaceutical art such as plasticizers, anti-tacking agents such astalc and coloring agents.

Coloring agents may be added for elegance and aesthetics or todifferentiate products and may be chosen, for example, from metal oxidepigments or Aluminum Lake dyes.

A coating composition may include an anti-tacking agent such as talc.Other examples of suitable anti-tacking agent are glycerol monostearate,calcium stearate, colloidal silicon dioxide, glycerin, magnesiumstearate, and aluminum stearate.

The compositions are typically formulated to be compatible and result instable products.

The formulation or composition may be used for treatment of a patient,for example, an animal and more particularly, a mammal. By mammal, ismeant any member of the class of Mammalia that is characterized by beinga vertebrate having hair and mammary glands. Examples include, withoutlimitation, dog, cat, rabbit, horse, pig, goat, cow, and human being.The formulation or composition of the present invention may beadministered to any animal patient or mammalian patient that is in needof treatment with a site specific, timed, pulsed, chronotherapeutic,extended, or controlled release of an active ingredient. In one example,a delivery formulation of the present invention is used for treating ahorse, a dog or a cat. In another example, a delivery formulation of thepresent invention is used for treating a human being.

A medical condition or overdose may be prevented or treated byadministering to a patient a formulation or composition comprising atherapeutically effective amount of an addictive substance with quickonset and sustained action of relief.

In certain examples of methods of preparing or using the saidformulation or composition, the administration in man or animal may beinternal, such as oral or parenteral. Such internal parenteraladministration includes but is not limited to intravascular,intramuscular, subcutaneous, intradermal, implantation, andintracavitary routes of administration, as well as application to theexternal surface of an internal bodily organ, such as during a surgicalor laparoscopic procedure. The administration may be topical, includingadministration to the skin or to a mucosal surface, including the oral,vaginal, rectal surfaces, or to the surface of the eye. Most typically,the formulation is orally administrable.

The formulation may also be in the form of a solid. The means and areaof application will depend on the particular condition that is beingtreated. The formulation may be dispensed using any suitable formulationand/or dispensing formulation. For example, it may be taken orally,implanted, or as a depot. It may be targeted at specific sites in thegastrointestinal tract (GU) or to specific organs. As another example,the formulation may also be applied transdermally in a pouch or patch.

Solid particles may be prepared by conventional techniques. They may bemilled to required size or surface area where necessary. The typicaltechnique is by dry or wet granulation or hot melt extrusion or rollercompaction of an active substance, controlled release agent(s) andexcipients such as solubilizing agents, emulsifying agents, suspendingagents, fillers, compression agents, stabilizers, pH altering agents,buffers, lubricants, disintegrants and glidants.

Fillers, such as lactose, and compression agents such asmicrocrystalline cellulose, lubricants such as magnesium stearate andglidants such silicone dioxide may, in certain examples, be included inthe core. The core onto which the coating is applied contains the activecomponent. The core may be a tablet, capsule, caplet, pellet, sphericalor irregular in shape. The core may be made up of multiple layers bypress coating or solution coating. The core may contain a loading dose.

In certain examples, swellable polymeric materials such as hydrogelsthat swell and expand significantly are included in the core.

Excipients may be homogenously mixed with an active ingredient in a coreparticle. Excipients may be selected from antiadherents, binders,diluents, emulsifying agents, suspending agents, compression agents,extrusion agents, pH altering agents, buffers, glidants, lubricants,solubilizers, wetting agents, surfactants, penetration enhancers,pigments, colorants, flavoring agents, sweeteners, antioxidants,acidulants, stabilizers, antimicrobial preservatives and binders.

Extrusion agents include, for example, copolyvidone; copovidone; VPNAccopolymer 60/40; copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate ina ratio of 6:4 by mass, Kollidon VA 64/Fine, Kollidon SR, Kollidon12/17P, Kollidon 25, Kollidon 30/90, Soluplus (graft copolymer ofpolyethylene glycol, polyvinyl caprolactam and polyvinylacetate,Cremaphor RH 40.

Excipients are biologically inert ingredients, which enhance thetherapeutic effect. The filler or diluent (e.g. lactose or sorbitol) isa bulking agent, providing a quantity of material, which can accuratelybe formed into a tablet. The binders and adhesives (e.g. methylcellulose or gelatin) hold the ingredients together so that they form atablet and hold together. Lubricants (e.g. magnesium stearate or calciumstearate) are added to improve powder flow so that the die fillsaccurately; they also reduce the friction between the tablet and themachine so that the process progresses smoothly and uniformly.

Anti-adherents are used to reduce the adhesion between the powder(granules) and the punch faces and thus prevent tablet sticking to thepunches.

Binders hold the ingredients in a tablet together. Binders ensure thattablets and granules can be formed with required mechanical strength.Binders may be selected from starches, sugars, and cellulose or modifiedcellulose such as hydroxypropyl cellulose, lactose, or sugar alcoholslike xylitol, sorbitol or maltitol. Solution binders are dissolved in asolvent (for example water or alcohol and used in wet granulationprocesses. Examples of solution binders are gelatin, cellulose,cellulose derivatives, polyvinyl pyrrolidone, starch, sucrose andpolyethylene glycol. Dry binders are added to a powder blend, eitherafter a wet granulation step, or as part of a direct powder compression.Examples of dry binders are cellulose, methyl cellulose, polyvinylpyrrolidone, polyethylene glycol. A commonly used binder or compressionagent is microcrystalline cellulose.

Microcrystalline and powdered cellulose products are sold under thetradenames Avicel™ PH (FMC Corporation, Philadelphia, Pa.) and SolkaFloc™ (Penwest Company, Patterson N.Y.). Microcrystalline cellulose maybe used in various techniques such as direct compression, drygranulation, wet granulation, or extrusion-spheronization.

Compression agents are materials that may be compacted. Compressionagents may be added to increase the overall hardness of a core particle.Compression agents have inherently high compactibility due to propertiesof plastic deformation and limited elastic recovery. Non-limitingexamples of materials that find use as compression agents aremicrocrystalline cellulose, silicified microcrystalline cellulose (forexample Prosolv™ produced by JRS Pharma), oxidized polyethylene, calciumhydrogen phosphate dehydrate, dextrate, or sugar.

Fillers or diluents are added for bulk to fill out the size of a tabletor capsule, making it practical to produce and convenient for theconsumer to use. Fillers/diluents are typically inert, compatible withthe other components of the formulation, non-hygroscopic, soluble,relatively cheap, compactible, and typically tasteless or pleasanttasting. Plant cellulose (pure plant filler) is a popular filler intablets or hard gelatin capsules. Dibasic calcium phosphate is anotherpopular tablet filler. A range of vegetable fats and oils can be used insoft gelatin capsules.

Other examples of fillers include: lactose, sucrose, glucose, mannitol,sorbitol, and, calcium carbonate. Fillers/diluents are typicallyselected from microcrystalline cellulose, plant cellulose, calciumphosphate, mannitol, sorbitol, xylitol, glucitol, ducitol, inositiol,arabinitol; arabitol, galactitol, iditol, allitol, fructose, sorbose,glucose, xylose, trehalose, allose, dextrose, altrose, gulose, idose,galactose, talose, ribose, arabinose, xylose, lyxose, sucrose, maltose,lactose, lactulose, fucose, rhamnose, melezitose, maltotriose, andraffinose. Typical sugars include mannitol, lactose, sucrose, sorbitol,trehalose, glucose.

Glidants are used to improve the flowability of the powder or granulesor both. Some examples of glidant(s) are silicon dioxide, starch,calcium silicate, Cabosil, Syloid, and silicon dioxide aerogels.Typically, silicon dioxide is used.

Lubricants prevent ingredients from clumping together and from stickingto the tablet punches or capsule-filling machine. Lubricants also ensurethat tablet formation and injection can occur with low friction betweenthe solid and die wall. Some examples of lubricant(s) are alkalistearates such as magnesium stearate, calcium stearate, zinc stearate,polyethylene glycol, adipic acid, hydrogenated vegetable oils, sodiumchloride, sterotex, glycerol monostearate, talc, polyethylene glycol,sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, sodiumstearyl fumarate, light mineral oil and the like may be employed. Waxyfatty acid esters, such as glyceryl behenate, sold as “Compritol”products, can be used. Other useful commercial lubricants include“Stear-O-Wet” and “Myvatex TL”. Common minerals like talc or silica, andfats, e.g. vegetable stearin, glycerol monostearate, magnesium stearateor stearic acid are typically used lubricants.

Sorbents are used for moisture proofing by limited fluid sorbing (takingup of a liquid or a gas either by adsorption or by absorption) in a drystate.

Surfactants, wetting agents and solubilisers such as glycerolmonostearate, cetostearyl alcohol, cetomacrogol emulsifying wax,sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol etherssuch as cetomacrogol 1000), polyoxyethlylene castor oil derivatives,polyoxyethylene sorbitan fatty acid esters (e.g., TWEEN™),polyoxyethylene stearates, sodium dodecylsulfate, Tyloxapol (a nonionicliquid polymer of the alkyl aryl polyether alcohol type, also known assuperinone or triton) is another useful solubilisers. Most of thesesolubilisers, wetting agents and surfactants are known pharmaceuticalexcipients and are described in detail in the Handbook of PharmaceuticalExcipients, published jointly by the American Pharmaceutical Associationand The Pharmaceutical Society of Great Britain (The PharmaceuticalPress, 1986).

Typical wetting agents include tyloxapol, poloxamers such as PLURONIC™F68, F127, and F108, which are block copolymers of ethylene oxide andpropylene oxide, and polyxamines such as TETRONIC™ 908 (also known asPOLOXAMINE™ 908), which is a tetrafunctional block copolymer derivedfrom sequential addition of propylene oxide and ethylene oxide toethylenediamine (available from BASF), dextran, lecithin, dialkylestersof sodium sulfosuccinic acid such as AEROSOL™ OT, which is a dioctylester of sodium sulfosuccinic acid (available from American Cyanimid),DUPONOL™ P, which is a sodium lauryl sulfate (available from DuPont),TRITON™ X-200, which is an alkyl aryl polyether sulfonate (availablefrom Rohm and Haas), TWEEN™ 20 and TWEEN™ 80, which are polyoxyethylenesorbitan fatty acid esters (available from ICI Specialty Chemicals),Carbowax 3550 and 934, which are polyethylene glycols (available fromUnion Carbide), Crodesta F-110, which is a mixture of sucrose stearateand sucrose distearate, and Crodesta SL-40 (both available from CrodaInc.), and SA90HCO, which is C₁₈H₃₇—CH₂ (CON(CH₃)CH₂(CHOH)₄CH₂OH)₂.

Wetting agents which have been found to be particularly useful, includeTetronic 908, the Tweens, Pluronic F-68 and polyvinylpyrrolidone. Otheruseful wetting agents include decanoyl-N-methylglucamide;n-decyl-β-D-glucopyranoside; n-decyl-β-D-maltopyranoside;n-dodecyl-β-D-glucopyranoside; n-dodecyl-β-D-maltoside;heptanoyl-N-methylglucamide; n-heptyl-β-D-glucopyranoside;n-heptyl-β-D-thioglucoside; n-hexyl-β-D-glucopyranoside;nonanoyl-N-methylglucamide; n-octyl-β-D-glucopyranoside;octanoyl-N-methylglucamide; n-octyl-β-D-glucopyranoside; andoctyl-β-D-thioglucopyranoside. Another typical wetting agent isp-isononylphenoxypoly(glycidol), also known as Olin-10G or Surfactant10-G (commercially available as 10G from Olin Chemicals). Two or morewetting agents can be used in combination.

The pharmaceutical formulation or formulation may further include apegylated excipient. Such pegylated excipients include, but are notlimited to, pegylated phospholipids, pegylated proteins, pegylatedpeptides, pegylated sugars, pegylated polysaccharides, pegylatedblock-co-polymers with one of the blocks being PEG, and pegylatedhydrophobic compounds such as pegylated cholesterol. Representativeexamples of pegylated phospholipids include 1,2-diacyl1-sn-glycero-3-phosphoethanolamine-N-[Poly(ethylene glycol) 2000] (“PEG2000 PE”) and1,2-diacyl-sn-glycero-3-phosphoethanolamine-N-[-Poly(ethylene glycol)5000](“PEG 5000 PE”), where the acyl group is selected, for example,from dimyristoyl, dipalmitoyl, distearoyl, diolcoyl, and1-palmitoyl-2-oleoyl.

Additional excipients may be included in the formulation of the presentinvention. Further examples of excipients can include pigments,colorants, flavoring agents, preservatives and sweetners. Flavors andcolors are added to improve the taste or appearance of a formulation.Some typical preservatives used in pharmaceutical formulations areantioxidants such as vitamin A, vitamin E, vitamin C, and selenium,amino acids such as cysteine and methionine, citric acid and sodiumcitrate, or synthetic preservatives such as methyl paraben and propylparaben. Sweeteners are added to make the ingredients more palatable,especially in chewable tablets such as antacid or liquids like coughsyrup. Sugar may be used to disguise unpleasant tastes or smells. Whilefor addictive substances bittering agents may be added make theadministration of a non-intact form objectionable.

One skilled in the art can select appropriate excipients for use in theformulation of the present invention.

The formulation may comprise an excipient that is a swellable materialsuch as a hydrogel in amounts that can swell and expand. Examples ofswellable materials include polyethylene oxide, hydrophilic polymersthat are lightly cross-linked, such cross-links being formed by covalentor ionic bond, which interact with water and aqueous biological fluidsand swell or expand to some equilibrium state. Swellable materials suchas hydrogels exhibit the ability to swell in water and retain asignificant fraction of water within its structure, and whencross-linked they will not dissolve in the water. Swellable polymers canswell or expand to a very high degree, exhibiting a 2 to 50 fold volumeincrease. Specific examples of hydrophilic polymeric materials includepoly(hydroxyalkyl methacrylate), poly(N-vinyl-2-pyrrolidone), anionicand cationic hydrogels, polyelectrolyte complexes, poly(vinyl alcohol)having a low acetate residual and cross-linked with glyoxal,formaldehyde, or glutaraldehyde, methyl cellulose cross-linked withdialdehyde, a mixture of cross-linked agar and carboxymethyl cellulose,a water insoluble, water-swellable copolymer produced by forming adispersion of finely divided copolymer of maleic anhydride with styrene,ethylene, propylene, butylene, or isobutylene cross-linked with from0.001 to about 0.5 moles of a polyunsaturated cross-linking agent permole of maleic anhydride in the copolymer, water-swellable polymers ofN-vinyl lactams, cross-linked polyethylene oxides, and the like. Otherexamples of swellable materials include hydrogels exhibiting across-linking of 0.05 to 60%, hydrophilic hydrogels known as Carbopolacidic carboxy polymer, Cyanamer™ polyacrylamides, cross-linkedwater-swellable indene-maleic anhydride polymers, Good-rite™ polyacrylicacid, starch graft copolymers, Aqua-Keeps™ acrylate polymer, diestercross-linked polyglucan, and the like. Methods for testing swellablematerials with regards to polymer imbibition pressure and hydrogel-waterinterface interaction are described in U.S. Pat. No. 4,327,725.

In a certain example, the formulation may be coated with salt forming,and/or ion exchanging resin, and/or a non-disintegrating and/ornon-semi-permeable coat. Materials useful for forming thenon-disintegrating non-semi-permeable coat are ethylcellulose,polymethylmethacrylates, methacrylic acid copolymers and mixturesthereof.

In yet another embodiment, the formulation is coated with anon-disintegrating semipermeable coat. Materials useful for forming thenon-disintegrating semipermeable coat are cellulose esters, cellulosediesters, cellulose triesters, cellulose ethers, cellulose ester-ether,cellulose acylate, cellulose diacylate, cellulose triacylate, celluloseacetate, cellulose diacetate, cellulose triacetate, cellulose acetatepropionate, and cellulose acetate butyrate. Other suitable polymers aredescribed in U.S. Pat. Nos. 3,845,770, 3,916,899, 4,008,719, 4,036,228and 4,612,008. The most typical non-disintegrating semipermeable coatingmaterial is cellulose acetate comprising an acetyl content of 39.3 to40.3%, commercially available from Eastman Fine Chemicals.

In an alternative embodiment, the non-disintegrating semipermeable ornon-disintegrating non-semi-permeable coat can be formed from theabove-described polymers and materials that will form pores or channelsin the coat. The pore forming agents or channeling agents dissolve oncontact with fluid and form passages through which fluid and activepharmaceutical ingredient(s) can move through the coat. The pore formingagent or channeling agent can be a water-soluble material or an entericmaterial. Some general examples of pore forming agents or channelingagents are water soluble materials such as cellulose ethers,polyethylene glycols or microcrystalline cellulose. Some furtherexamples of pore forming agents or channeling agents are sodiumchloride, potassium chloride, lactose, sucrose, sorbitol, mannitol,polyethylene glycol (PEG), for example PEG 600, polyvinyl pyrolidone,propylene glycol, hydroxypropyl cellulose, hydroxypropyl methycellulose,hydroxypropyl methycellulose phthalate, cellulose acetate phthalate,polyvinyl alcohols, methacrylic acid copolymers and mixtures thereof.

The active pharmaceutical ingredient(s) that are water-soluble or thatare soluble under intestinal conditions may also be used to create poresin the coat.

The pore forming agent comprises approximately 0 to about 75% of thetotal weight of the coating, most typically about 0.5% to about 25% ofthe total weight of the coating. The pore-forming agent dissolves orleaches from the coat to form pores in the coat for the fluid to enterthe core and dissolve the active ingredient.

As used herein the term pore includes an aperture, orifice, bore,channel, hole, a discrete area of weakness or as created by soluble orleachable materials.

Method of Making the Formulations

The formulations can be made by any known methods. For example, the corecan be made by blending and direct compression without wet granulation;by hot melt extrusion; by hot melt granulation; by roll compaction,slugging or a chilsonator; and/or by extrusion spheronization. A loadingdose or any coating may be press coated onto at least a portion of thecore as a separate layer(s).

In some embodiments, the loading dose is applied by spraying coating,dry coating, press coating, encapsulation, or by a combination of thesemethods.

In a specific example, an acid labile coating is prepared by adding anacid labile polymer and anti-tacking agent to an organosolvent oraqueous system and mixing until homogenously dissolved or dispersedusing a low or high shear mixer. The acid labile coating may be appliedto a core using standard coating methodology. Likewise, an alkalinizingcoat is prepared by adding an alkalinizing agent and a film coatingsystem such as Opadry to a solvent and mixing until homogenouslydissolved or dispersed. The alkalinizing coating may be applied to theacid labile coating using standard coating methodology.

The alkalinizing coat contains at least one alkalinizing agent that iscapable of undergoing the following neutralization with stomach acid:

MX₂+2HCl→MCl₂+2HX or MX₃+3HCl→MCl₃+3HX

where M is a metal ion (e.g. alkaline earth metal; alkali metal;aluminum; etc.) and X is a basic ion (e.g. hydroxide; silicate; oxide;carbonate; citrate, acetate; etc.).

In another example, a base labile coating is prepared by adding a baselabile polymer and anti-tacking agent to an organosolvent or aqueoussystem and mixing until homogenously dissolved or dispersed using a lowor high shear mixer. The base labile coating may be applied to a coreusing standard coating methodology. Likewise, an acidfying coat isprepared by adding an acidifying agent to a solvent and mixing untilhomogenously dissolved or dispersed. The acidifying coating may beapplied to the base labile coating using standard coating methodology. Afurther base labile coat is prepared by adding a base labile polymer anda film coating system such as Opadry to a solvent and mixing untilhomogenously dissolved or dispersed. The base labile coat may be appliedto acidifying coat using standard coating methodology.

The formulations described herein may contain one or more activesubstance, or specifically one or more opioid agonist or narcoticanalgesic or abuse-able substances, may be made by any method whereinthe particle size or surface area of active ingredient and/or inactiveingredient, quantity or ratio and type of loading dose, controlledrelease agents, external coat(s) and excipients is optimum to form aformulation with quick onset of action and sustained action thereafterwhile still capable of abuse resistant properties when ingested inhigher than prescribed or recommended doses.

Typically, the entire quantity of the core formulation is dry mixed andhomogeneously blended, and made into a solid unit (e.g. tablet, bead,compressed granules formed into any shape, etc.). Thereafter, the acidlabile coating is applied directly on the core by press coating,solution coating, or spraying as a layer, for example, such that theacid labile coating surrounds or substantially surrounds the tabletsufficiently to inhibit release of the active substance from the core ina non-acidic environment, while allowing release of the active substancein an acidic environment. Next, the alkalinizing coating is applieddirectly on the acid labile coating by press coating, solution coating,or spraying as a layer, for example, such that the alkalinizing coatingis present on the tablet in an amount sufficient to raise the pH of theenvironment when a threshold number of tablets are ingested. A coldprocess under room temperature conditions is typical, however solidsubstances may be heated to their liquid state prior to incorporation,using such methods as hot melt extrusion.

Alternatively, the formulation may be processed in a jacketed vessel,which allows precise control of the processing temperature. Otherpharmaceutically acceptable additives, such as those described above,may be incorporated before, after, or during the addition of controlledrelease agents or active substances. Wet granulation can also be used.

The solid particles may be of a size and/surface area such that theactive ingredient maintains very intimate and close proximity to thepolymers and homogeneity. The solid particles may take any convenientform, including, for example, granules, spheroids, pellets,microspheres, nanospheres, microcapsules, or crystals and can beprepared by wet or dry granulation, by extrusion spheronization, by hotmelt extrusion, by powder or solution layering, by microencapsulationtechniques, by milling and compression techniques or other suitableknown techniques. In certain examples, different types of coats may beapplied to the formulation.

In certain examples, the particle size of solid materials is less thanabout 1000 microns. In certain other examples, the particle size ofsolid materials is less than about 500, 200, 100, or 50 microns and theformulation maintains very intimate and close proximity to the polymersand homogeneity especially when crushed. In certain further, examplesthe solid particles are sufficiently small and have large surface areasuch that they are in very intimate and close proximity and homogeneitywith one another. These types of formulations may resist abuse orinadvertent misuse.

In certain examples, capsules, for example, soft or hard capsules,envelop the formulations. While both soft and hard capsules may be used,hard capsules may be particularly useful. In certain examples, thecapsule is made by applying a polymeric coat of material that result ina plastic or elastic shell in any shape (e.g. pod-like envelope). Itcould also be a hard gelatin capsule or be made of a metal or alloy ofmetals, cellulose ether, or be of vegetable or animal origin.

One skilled in the art will also know that capsules made from materialsother than gelatin may be used. For example, U.S. Patent ApplicationPublication No. 2006/0099246 pertains to a non-gelatin soft capsulesystem having a predominantly starch and gelling carrageenan basedshell. Carrageenan is a collective term for polysaccharides prepared byalkaline extraction (and modification) from red seaweed (Rhodophycae),mostly of genus Chondrus, Eucheuma, Gigartina and Iridaea. Differentseaweeds produce different carrageenans. Carrageenan consists ofalternating 3-linked-β-D-galactopyranose and4-linked-α-D-galactopyranose units. Most, if not all, of the galactoseunits are substituted with sulfate ester groups. In another example, USPatent Appln. Pub. No. 2006/0004193 (Muller) published Jan. 5, 2006relates to a tough-elastic material based on starch, which on the onehand has high impact toughness at low humidity, and on the other handstill has a high modulus of elasticity at high humidity and has a highelongation capacity in a broad range of humidity and on account of itsproperty profile is suited to use as edible film and for the packagingof active ingredients, as well as high-quality substitution of gelatinin the area of soft and hard capsules. As another example, PCTPublication WO 01/37817 describes a soft capsule based on thermoplasticstarch (TPS) with high softener content. As another example, U.S. PatentApplication Publication No. 2005/0196436 relates to a method ofproducing a film-forming blend of different acyl gellan gums with starchhaving similar textural and functional properties compared to gelatin.As another example, U.S. Patent Application Publication No. 2007/0077293(Park) published Apr. 5, 2007 relates to a film-forming composition forhard capsules, comprising 7-12% by weight of starch, 1-6% by weight of aplasticizer, 0.7-3% by weight of a gelling agent, and 79-91.3% by weightof water. As another example, U.S. Patent Application Publication No.2006/0153909 relates to hard capsules made of a base material containinga cellulose derivative including, for example, one or more ofhydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose,hydroxyethyl cellulose, hydroxypropyl methylcellulose phthalate,hydroxypropyl methylcellulose acetate succinate, carmelose,carboxymethylethyl cellulose, cellulose acetate phthalate, andethylcellulose. Also, additives such as a gelling agent, a gelling aid,a colorant, a plasticizer, an emulsifier, a dispersant, and apreservative may be added to the capsule base material. As yet anotherexample, U.S. Patent Application Publication No. 2005/0186268 describesa hard capsule made mainly of a polymer or copolymer obtained bypolymerizing or copolymerizing at least one polymerizable vinyl monomerin the presence of polyvinyl alcohol and/or a derivative thereof. Stillmany other examples exist, as will be recognized by the skilled person.

In certain examples, a controlled release formulation may be incombination with a non-controlled release formulation containing anopioid antagonist and/or an immediate release non-narcotic analgesic orother pharmaceutically active substances or filled into a capsule ordispensing formulation with a non-controlled release compositioncontaining an opioid antagonist and/or an immediate release non-narcoticanalgesic or other pharmaceutically active substances.

In certain examples, dissolution using a USP dissolution tester is notsignificantly different by modifying the rotation speed of the basket orpaddle in the speed range from about 25 rpm to about 150 rpm, or atabout 50 rpm and about 100 rpm or at about 50 rpm and about 75 rpm or atabout 100 rpm and about 150 rpm. The rotation speed does not generallyinteract with or compromise the integrity of the formulation and releasemechanism, at least in the first one to six hours. When many unit dosageforms are included together in the tester for long periods of time,upwards of, for example, 12 or more hours, some mechanically-induceddisintegration of the unit dosage forms may be observed. Formulationsthat meet these requirements perform consistently in thegastrointestinal tract without fear of collapse or disintegration. Theseare typically not perturbed, crushed or damaged by gastrointestinaltract content, resident time or motility.

When introducing elements disclosed herein, the articles “a”, “an”,“the”, and “said” are intended to mean that there may be one or more ofthe elements.

Any range described herein is understood to include any incrementalranges or individual values therebetween.

In understanding the scope of the present application, the term“comprising” and its derivatives, as used herein, are intended to beopen ended terms that specify the presence of the stated features,elements, components, groups, integers, and/or steps, but do not excludethe presence of other unstated features, elements, components, groups,integers and/or steps. The foregoing also applies to words havingsimilar meanings such as the terms, “including”, “having” and theirderivatives. It will be understood that any aspects described as“comprising” certain components may also “consist of” or “consistessentially of,” wherein “consisting of” has a closed-ended orrestrictive meaning and “consisting essentially of” means including thecomponents specified but excluding other components except for materialspresent as impurities, unavoidable materials present as a result ofprocesses used to provide the components, and components added for apurpose other than achieving the technical effects described herein. Forexample, a composition defined using the phrase “consisting essentiallyof” encompasses any known pharmaceutically acceptable additive,excipient, diluent, carrier, and the like. Typically, a compositionconsisting essentially of a set of components will comprise less than 5%by weight, typically less than 3% by weight, more typically less than 1%by weight of non-specified components.

It will be understood that any component defined herein as beingincluded may be explicitly excluded from the claimed invention by way ofproviso or negative limitation.

Finally, terms of degree such as “substantially”, “about” and“approximately” as used herein mean a reasonable amount of deviation ofthe modified term such that the end result is not significantly changed.These terms of degree should be construed as including a deviation of atleast ±5% of the modified term if this deviation would not negate themeaning of the word it modifies.

The above disclosure generally describes the present invention. A morecomplete understanding can be obtained by reference to the followingspecific Examples. These Examples are described solely for purposes ofillustration and are not intended to limit the scope of the invention.Changes in form and substitution of equivalents are contemplated ascircumstances may suggest or render expedient. Although specific termshave been employed herein, such terms are intended in a descriptivesense and not for purposes of limitation.

EXAMPLES Example 1. Comparison of the Effects of Different AlkalinizingAgents on the pH of an Acidic Solution

Various alkalinizing agents were added to a solution of 0.1 N HCl with astarting pH of 2.0 and the pH of the solution was tested at differenttime points. The purpose of these experiments was to provide variousexamples of alkalinizing agents in varying amounts that could be used toraise the pH of stomach acid sufficiently to reduce dissolution of anacid labile coat. From these experiments, it was concluded that oneskilled in the art, based on these examples and teachings, would be ableto vary the alkalinizing agent and amounts to yield the desired result.

Table 1 and FIG. 1 show the effects of magnesium hydroxide over a 60minute timecourse in amounts ranging from 60-120 mg/320 ml solution andfrom 60-240 mg/500 ml solution. From this timecourse, it can be seenthat all tested amounts were able to raise the pH of the solution above2.0 over the times tested, however, the 100 mg/320 ml (0.3125 mg/ml),180 mg/500 ml (0.36 mg/ml), 120 mg/320 ml (0.375 mg/ml), 200 mg/500 ml(0.4 mg/ml), and 240 mg/500 ml (0.48 mg/ml) all rapidly raised the pH ofthe solution to neutral or higher.

TABLE 1 Effect of magnesium hydroxide on the pH of a solution of 0.1NHCl with a starting pH of 2.0. Time 60 mg per 90 mg per 100 mg per 120mg per 60 mg per 100 mg per 120 mg per 180 mg per 200 mg per 240 mg per(Min) 320 mL 320 mL 320 mL 320 mL 500 mL 500 mL 500 mL 500 mL 500 mL 500mL 0 2.03 2.05 2.03 2.05 2.01 2.03 2.01 2.05 2.03 2.00 1 2.17 2.19 2.152.25 2.06 2.10 2.10 2.34 2.19 2.17 2 2.29 2.37 2.36 2.49 2.12 2.21 2.212.56 2.48 2.54 3 2.41 2.55 2.53 2.87 2.17 2.33 2.35 3.09 2.81 3.14 42.47 2.77 2.74 3.54 2.18 2.38 2.44 3.90 3.54 5.90 5 2.48 3.06 3.07 5.752.19 2.40 2.52 5.69 5.42 7.73 6 2.48 3.13 3.39 6.65 2.19 2.40 2.57 6.286.63 9.09 7 2.49 3.22 3.73 7.81 2.19 2.41 2.59 6.64 7.99 9.35 8 2.493.28 4.26 8.55 2.19 2.41 2.59 7.01 8.86 9.47 9 2.49 3.31 5.41 8.83 2.192.41 2.59 7.61 9.07 9.54 10 2.49 3.33 5.86 8.94 2.19 2.41 2.59 8.25 9.189.59 20 2.50 3.34 6.51 9.20 2.19 2.41 2.60 9.07 9.41 9.71 30 2.50 3.376.75 9.23 2.19 2.41 2.60 9.14 40 2.50 3.35 6.92 9.27 2.41 2.60 9.16 502.50 3.35 7.01 9.24 2.41 9.19 60 2.53 3.36 7.09 2.41 9.20

Table 2 and FIG. 2 show the effects of magnesium oxide and calciumcarbonate over a 60 minute timecourse in various amounts. From thistimecourse, it can be seen that, again, all tested amount were able toraise the pH of the solution above 2.0 over the times tested, however,the 160 mg/320 ml (0.5 mg/ml) magnesium hydroxide and the 240 mg/320 ml(0.75 mg/ml) calcium carbonate both rapidly raised the pH of thesolution to neutral or higher.

TABLE 2 Effect of magnesium oxide and calcium carbonate on the pH of asolution of 0.1N HCl with a starting pH of 2.0. Time MgO 40 mg MgO 80 mgMgO 160 mg MgO 160 mg CaCO₃ 60 mg CaCO₃ 120 mg CaCO₃ 240 mg (Min) per320 mL per 320 mL per 320 mL per 500 mL per 320 mL per 320 mL per 320 mL0 2.01 1.99 1.99 1.98 2.00 2.03 2.02 1 2.01 2.00 2.05 2.00 2.14 2.283.14 2 2.03 2.02 2.14 2.02 2.18 2.31 4.32 3 2.08 2.05 2.24 2.05 2.182.31 4.79 4 2.10 2.06 2.35 2.07 2.18 2.31 5.00 5 2.13 2.08 2.47 2.122.18 2.31 5.16 6 2.16 2.10 2.60 2.15 2.18 2.31 5.27 7 2.19 2.12 2.712.18 2.18 2.29 5.37 8 2.22 2.13 2.83 2.22 2.18 2.29 5.44 9 2.23 2.152.95 2.24 2.18 2.29 5.51 10 2.24 2.17 3.07 2.27 2.19 2.27 5.58 20 2.302.30 8.16 2.54 2.19 2.26 5.96 30 2.33 2.40 9.30 2.62 2.26 6.35 40 2.392.48 9.54 2.74 2.25 6.99 50 2.34 2.55 2.86 2.25 7.48 60 2.34 2.63 2.962.25 7.65

Table 3 and FIG. 3 show the effects of sodium bicarbonate over a 60minute timecourse in amounts of 20 mg/320 ml solution and 40 mg/320 mlsolution. From this timecourse, it can be seen that both tested amountswere able to raise the pH of the solution above 2.0 over the timestested, however, neither amount tested was sufficient to raise the pH toneutral or higher.

TABLE 3 Effect of sodium bicarbonate on the pH of a solution of 0.1N HClwith a starting pH of 2.0. Time (Min) 20 mg per 320 mL 40 mg per 320 mL0 2.02 2.05 1 2.04 2.08 2 2.05 2.08 3 2.05 2.08 4 2.05 2.08 5 2.05 2.096 2.05 2.09 7 2.05 2.09 8 2.05 2.09 9 2.05 2.09 10 2.05 2.09 20 2.052.09 30 2.05 2.09 40 2.05 2.09 50 2.05 2.09 60 2.05 2.09

Table 4 and FIG. 4 show the effects of magnesium oxide over a 60 minutetimecourse in amounts of 80-120 mg/200 ml solution. Additionally shownis a 60 minute timecourse for an amount of 80 mg magnesium oxide ingranular form in 200 ml solution. From this timecourse, it can be seenthat all tested amounts and forms were able to rapidly raise the pH ofthe solution to neutral or higher, with the granular form laggingslightly behind the powder form of magnesium oxide.

TABLE 4 Effect of magnesium oxide in powder or granular form on the pHof a solution of 0.1N HCl with a starting pH of 2.0. Time, min 80 mg 100mg 120 mg 80 mg, Granular 1 2.50 2.37 4.45 2.17 2 4.09 2.37 5.50 2.30 35.72 2.37 6.01 2.45 4 6.21 2.37 6.97 2.75 5 6.67 2.37 8.21 3.37 6 7.223.52 8.21 5.50 7 7.98 3.52 8.21 6.04 8 8.42 3.52 8.21 6.38 9 8.44 3.528.21 6.74 10 10.13 3.52 8.21 7.05 20 10.13 5.00 8.21 7.50 30 8.66 6.508.21 9.14 40 10.13 8.09 8.21 9.47 50 10.13 9.02 8.21 9.47 60 10.13 9.028.21 9.47

Table 5 and FIG. 5 show the effects of magnesium hydroxide over a 60minute timecourse in amounts of 60-100 mg/200 ml solution. From thistimecourse, it can be seen that all tested amount were able to raise thepH of the solution above 2.0 over the times tested, however, the 71mg/200 ml (0.355 mg/ml), 81 mg/200 ml (0.405), and 100 mg/200 ml (0.5mg/ml) magnesium hydroxide all raised the pH of the solution to neutralor higher.

TABLE 5 Effect of magnesium hydroxide on the pH of a solution of 0.1NHCl with a starting pH of 2.0. Time, min 100 mg 81 mg 71 mg 60 mg 1 2.502.50 2.45 2.50 2 3.56 3.01 2.83 2.66 3 5.25 3.66 3.18 2.83 4 5.58 5.013.48 2.92 5 5.80 5.30 3.70 2.96 6 5.97 5.50 3.91 2.99 7 6.10 5.65 4.132.99 8 6.22 5.80 4.31 3.00 9 6.34 5.87 4.48 3.00 10 6.43 5.92 4.63 3.0020 7.70 6.60 5.40 3.01 30 8.69 6.92 5.72 3.01 40 8.90 7.25 6.05 3.01 509.10 7.51 6.73 3.01 60 9.10 8.00 7.08 3.01

Table 6 and FIG. 6 show the effects of calcium carbonate over a 60minute timecourse in amounts of 120-140 mg/200 ml solution. From thistimecourse, it can be seen that all tested amount were able to raise thepH of the solution to near neutral or neutral.

TABLE 6 Effect of calcium carbonate on the pH of a solution of 0.1N HClwith a starting pH of 2.0. Time, min 140 mg 130 mg 120 mg 10 5.53 4.604.02 20 5.53 5.90 4.61 30 5.53 6.50 5.25 40 5.53 6.82 5.88 50 5.53 7.016.24 60 5.53 7.10 6.54

Table 7 and FIG. 7 show the effects of magnesium hydroxide and calciumcarbonate in combination over a 60 minute timecourse in amounts of50-71.25 mg magnesium hydroxide per 200 ml solution and from50.95-150.35 mg calcium carbonate per 200 ml solution. From thistimecourse, it can be seen that all tested amounts were able to raisethe pH of the solution to near neutral or higher.

TABLE 7 Effect of magnesium hydroxide and calcium carbonate incombination on the pH of a solution of 0.1N HCl with a starting pH of2.0. 50.82 mg Mg(OH)₂ + 50.47 mg Mg(OH)₂ + 50.0 mg Mg(OH)₂ + 71.09 mgMg(OH)₂ + 71.25 mg Mg(OH)₂ + Time, min 50.95 mg CaCO₃ 80.55 mg CaCO₃100.98 mg CaCO₃ 100.71 mg CaCO₃ 150.35 mg CaCO₃ 1 2.52 3.01 3.01 3.003.01 2 2.82 3.93 4.59 4.57 4.71 3 3.25 4.72 5.01 5.09 5.12 4 3.78 5.005.21 5.29 5.32 5 4.41 5.17 5.33 5.44 5.47 6 4.77 5.27 5.43 5.55 5.57 74.97 5.35 5.51 5.64 5.66 8 5.10 5.42 5.58 5.72 5.73 9 5.20 5.48 5.645.80 5.80 10 5.27 5.55 5.69 5.86 5.86 20 5.73 5.92 6.10 6.42 6.44 306.05 6.26 6.50 7.25 7.45 40 6.33 6.54 6.89 8.55 8.57 50 6.60 6.84 7.518.82 8.65 60 6.85 7.20 8.22 8.82 8.65

Table 8 and FIG. 8 show the effects of 930 mg sodium citrate, 200 mgsodium acetate, 100 mg L-arginine-HCl, 100 mg magnesium carbonate, and120 mg meglumine over a 60 minute timecourse in 200 ml solution. Fromthis timecourse, it can be seen that all tested amounts were able toraise the pH of the solution above the 2.0 starting point, however, thesodium citrate and the sodium acetate were able to raise the pH to above5.

TABLE 8 Effect of sodium citrate, sodium acetate, L-arginine- HCl,magnesium carbonate, and meglumine on the pH of a solution of 0.1N HClwith a starting pH of 2.0. 930 mg 200 mg 100 mg 100 mg Sodium SodiumArginine Magnesium 120 mg Time, min Citrate Acetate HCl CarbonateMeglumine 10 5.53 4.73 2.20 3.05 2.16 20 5.53 4.96 2.20 3.05 2.16 305.53 5.08 2.20 3.05 2.16 40 5.53 5.21 2.20 3.05 2.16 50 5.53 5.34 2.203.05 2.16 60 5.53 5.34 2.20 3.05 2.16

Table 9 and FIG. 9 show the effects of sodium carbonate over a 60 minutetimecourse in amounts of 11.13-81.68 mg/200 ml solution. From thistimecourse, it can be seen that all tested amount were able to raise thepH of the solution above the 2.0 starting point, and that 81.68 mgsodium carbonate was able to raise the pH of the 200 ml solution toabove neutral.

TABLE 9 Effect of sodium carbonate on the pH of a solution of 0.1N HClwith a starting pH of 2.0. Time (mins) 11.13 mg 30.11 mg 81.68 mg 0 2.662.57 2.73 1 2.80 3.21 9.02 2 2.80 3.24 9 3 2.80 3.25 8.97 4 2.80 3.258.95 5 2.80 3.26 8.93 10 2.80 3.27 8.83 15 2.80 3.27 8.81 20 2.80 3.278.5 60 2.80 3.27 8.25

Table 10 and FIG. 10 show the effects of sodium bicarbonate over a 40minute timecourse in amounts of 50 and 100 mg/200 ml solution. From thistimecourse, it can be seen that neither tested amount was sufficient toraise the pH of the 200 ml starting solution.

TABLE 10 Effect of sodium bicarbonate on the pH of a solution of 0.1NHCl with a starting pH of 2.0. Time (mins) 50 mg 100 mg 0 1.71 1.71 101.72 1.76 20 1.72 1.75 30 1.72 1.75 40 1.72 1.75

Table 11 and FIG. 11 show the effect of 10 mg sodium lauryl sulfate overa 30 minute timecourse in 200 ml acidic solution. From this timecourse,it can be seen that this amount of sodium lauryl sulfate wasinsufficient to substantially raise the pH of the solution beyond the2.0 starting point.

TABLE 11 Effect of sodium lauryl sulfate on the pH of a solution of 0.1NHCl with a starting pH of 2.0. Time (mins) 10 mg (10.22 mg actual) 02.67 1 2.68 2 2.68 3 2.68 4 2.67 5 2.67 6 2.67 7 2.67 8 2.67 9 2.67 102.67 20 2.67 30 2.67

Table 12 and FIG. 12 show the effect of 80 mg magnesium carbonate over a30 minute timecourse in 200 ml acidic solution. From this timecourse, itcan be seen that this amount of magnesium carbonate was sufficient toraise the pH of the solution to above 9.

TABLE 12 Effect of magnesium carbonate on the pH of a solution of 0.1NHCl with a starting pH of 2.0. Time (mins) 80 mg 0 2.73 1 4.78 2 6.09 36.57 4 7.44 5 8.64 6 8.92 7 9.03 8 9.09 9 9.13 10 9.17 20 9.26 30 9.26

Example 2. Preparation of Oxycodone HCl Overdose Resistant (ODR) 5 mgTablets

Formula for Core Ingredients % w/w Oxycodone HCl 2.50 Lactose 68.50Crospovidone 2.00 Microcrystalline cellulose 15.00 Starch 1500 10.00Stearic Acid 2.00

Formula for Acid Labile Coat* Ingredients % w/w Eudragit E 9.73 SodiumLauryl Sulfate 0.97 Talc 3.40 Stearic Acid 1.46 Simethicone Emulsion 30%2.81 Water 81.63 *345 g of coating suspension was made and applied to500 g of cores

Formula for Alkalinizing Coat* Ingredients % w/w Opadry White 10.00Magnesium Hydroxide 20.18 Water 69.82 *1000 g of coating suspension wasmade and applied to 500 g of acid labile-coated cores

Processing Techniques

Step 1a. Preparation of Granules for the Core:

All the ingredients with the exception of the stearic acid from the coreformula were charged into a high shear granulator and dry mixed for lessthan 10 minutes. The dry mixed granules were discharged into a PatersonKelly V-Blender. The stearic acid was then added to the V-Blender. Thegranules were blended for less than 10 minutes.

Step 1b. Preparation of the Core (Immediate Release Tablets):

The cores are tablets made from the granules prepared in Step 1a. Arotary press was set-up to produce capsule shaped tablets each weighingabout 200 mg (a Manesty tablet press with 16 stations was used).Granules from Step 1a were charged into a feed hopper and the tablet wasproduced from the double rotary press by applying suitable compressionforce to give tablets of required thickness, hardness and friability.

Step 2. Preparation of a coating suspension of the ingredients of theacid labile coat:

(I) Water was added into a stainless steel vessel followed by sodiumlauryl sulfate until dissolved. To this was added stearic acid followedby Eudragit E and talc, step-by-step, while stirring vigorously with ahigh shear mixer until all ingredients were finely dispersed in asuspension. (II) Simethicone emulsion was added to the Eudragit Esuspension while stirring using a high shear mixer.

Step 3. Application of the Coating Suspension from Step 2 to Form anAcid Labile Coat Surrounding the Tablet Cores from Step 1b:

Tablets from Step 1b were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 2 was applied to thetablet cores obtained from Step 1b, using a peristaltic pump and spraygun. The suspension was dried as a film onto the tablets, using heatedair drawn through the tablet bed from an inlet fan.

A sufficient amount of the suspension was applied to form about 8 mg/cm²to about 12 mg/cm² of the coat surrounding the tablet.

Step 4. Preparation of a Coating Suspension of the Ingredients of theAlkalinizing Coat:

(I) Water was added into a stainless steel vessel followed by OpadryWhite until no lumps are seen in the resulting suspension. (II) To avortex of this suspension was added magnesium hydroxide until finelydispersed.

Step 5. Application of the Coating Suspension from Step 4 to Form anAlkalinizing Coat Surrounding the Coated Tablet from Step 3:

Tablets from Step 3 were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 4 was applied to thetablets obtained from Step 3, using a peristaltic pump and spray gun.The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to a weight gain of about 50% wt/wt to about70% wt/wt of the coated tablet from Step 3.

Example 3. Dissolution Test of Coated Tablets from Example 2

Tablets from Example 2 were placed into 500 ml of a 0.01 N HCl solutionand were agitated with paddles at 100 rpm for various times at 37° C.Table 13 and corresponding FIGS. 13A and 13B show that increasingnumbers of tablets in the solution led to decreased dissolution of thetablets, both in terms of time and extent of total dissolution. FIGS.13C and 13D show images of 1 and 2 tablets, respectively, dissolvingcompletely after 1 hour. FIGS. 13E, 13F, 13G, and 13H show images of the3-6 tablet experiments, respectively, with the tablets remaining mostlyintact or completely intact (other than the alkalinizing coat) after 24hours.

It should be noted that at the longer ends of the timecourse, e.g., from22-24 hours, the tablets began to disintegrate from the mechanicaleffects of the paddles and tablets hitting one another. Therefore, theextent of dissolution seen in the higher number tablet experiments (forexample, from 10-100 tablets) appears to be an artefact and much lowerdissolution would be expected in a system without paddles (e.g., in thestomach).

TABLE 13 Comparative dissolution of different quantities of tablets madeaccording to Example 2 in 500 ml 0.01N HCl (pH 2.0). Number of tabletsin dissolution vessel and percent dissolved Time (hrs) 1 tab 2 tabs 3tabs 4 tabs 5 tabs 6 tabs 10 tabs 20 tabs 40 tabs 60 tabs 80 tabs 100tabs 0 0 0 0 0 0 0 0 0 0 0 0 0 1 91 93 65 29 14 6 0 0 0 0 0 0 2 91 92 6643 14 11 0 0 0 0 0 0 3 93 92 70 47 16 14 0 0 0 0 0 0 4 93 92 73 50 19 170 0 0 0 0 0 5 94 93 76 52 21 20 1 0 0 0 0 0 6 92 91 78 53 24 24 2 1 0 00 0 22 94 92 95 82 62 63 17 11 10 11 21 32 23 94 92 95 83 80 77 18 12 1012 23 30 24 93 94 95 84 66 65 18 13 10 13 22 31 Starting pH 2.0 2.0 2.02.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 Ending pH 9.25 9.31 9.30 9.31 9.289.27

Example 4. Preparation of Oxycodone HCl Overdose+Insufflation Resistant(ODIR) 5 mg Tablets

Formula for Core Ingredients % w/w Oxycodone HCl 2.50 Lactose 38.00Sodium Lauryl Sulfate 30.50 Crospovidone 2.00 Microcrystalline cellulose15.00 Starch 1500 10.00 Stearic Acid 2.00

Formula for Acid Labile Coat* Ingredients % w/w Eudragit E 9.73 SodiumLauryl Sulfate 0.97 Talc 3.40 Stearic Acid 1.46 Simethicone Emulsion 30%2.81 Water 81.63 *687.82 g of coating suspension was made and applied to500 g of cores

Formula for Alkalinizing Coat* Ingredients % w/w Opadry White 10.00Magnesium Hydroxide 20.18 Water 69.82 *1000 g of coating suspension wasmade and applied to 500 g of acid labile-coated cores

Processing Techniques

Step 1a. Preparation of Granules for the Core:

All the ingredients with the exception of the stearic acid from the coreformula were charged into a high shear granulator and dry mixed for lessthan 10 minutes. The dry mixed granules were discharged into a PatersonKelly V-Blender. The stearic acid was then added to the V-Blender. Thegranules were blended for less than 10 minutes.

Step 1b. Preparation of the Core (Immediate Release Tablets):

The cores are tablets made from the granules prepared in Step 1a. Arotary press was set-up to produce capsule shaped tablets each weighingabout 200 mg (a Manesty tablet press with 16 stations was used).Granules from Step 1a were charged into a feed hopper and the tablet wasproduced from the double rotary press by applying suitable compressionforce to give tablets of required thickness, hardness and friability.

Step 2. Preparation of a Coating Suspension of the Ingredients of theAcid Labile Coat:

(I) Water was added into a stainless steel vessel followed by sodiumlauryl sulfate until dissolved. To this was added stearic acid followedby Eudragit E and talc, step-by-step, while stirring vigorously with ahigh shear mixer until all ingredients were finely dispersed in asuspension. (II) Simethicone emulsion was added to the Eudragit Esuspension while stirring using a high shear mixer.

Step 3. Application of the Coating Suspension from Step 2 to Form anAcid Labile Coat Surrounding the Tablet Cores from Step 1b:

Tablets from Step 1b were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 2 was applied to thetablets obtained from Step 1b, using a peristaltic pump and spray gun.The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to form about 19 mg/cm² to about 25 mg/cm² ofthe coat surrounding the tablet.

Step 4. Preparation of a Coating Suspension of the Ingredients of theAlkalinizing Coat:

(I) Water was added into a stainless steel vessel followed by OpadryWhite until no lumps are seen in the resulting suspension. (II) To avortex of this suspension was added magnesium hydroxide until finelydispersed.

Step 5. Application of the Coating Suspension from Step 4 to Form anAlkalinizing Coat Surrounding the Coated Tablet from Step 3:

Tablets from Step 3 were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 4 was applied to thetablets obtained from Step 3, using a peristaltic pump and spray gun.The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to a weight gain of about 50% wt/wt to about70% wt/wt of the coated tablet from Step 3.

Example 5. Dissolution Test of Coated Tablets from Example 4

Tablets from Example 4 were placed into 500 ml of a 0.01 N HCl solutionand were agitated with paddles at 100 rpm for various times at 37° C.Table 14 and corresponding FIGS. 14A and 14B show that increasingnumbers of tablets in the solution led to decreased dissolution of thetablets, both in terms of time and extent of total dissolution. FIGS.14C and 14D show images of 1 and 2 tablets, respectively, dissolvingcompletely after 1 hour. FIGS. 14E, 14F, 14G, and 14H show images of the3-6 tablet experiments, respectively, with the tablets remaining mostlyintact or completely intact (other than the alkalinizing coat) after 24hours.

It should be noted that at the longer ends of the timecourse, e.g., from22-24 hours, the tablets began to disintegrate from the mechanicaleffects of the paddles and tablets hitting one another. Therefore, theextent of dissolution seen in the higher number tablet experiments (forexample, from 10-100 tablets) appears to be an artefact and much lowerdissolution would be expected in a system without paddles (e.g., in thestomach).

The thicker acid labile coating on these tablets as compared to those ofExample 2 appears to have protected them somewhat from the mechanicaldisintegration caused by the paddles and other tablets hitting oneanother.

TABLE 14 Comparative dissolution of different quantities of tablets madeaccording to Example 2 in 500 ml 0.01N HCl (pH 2.0). Number of tabletsin dissolution vessel and percent dissolved Time (hrs) 1 tab 2 tabs 3tabs 4 tabs 5 tabs 6 tabs 10 tabs 20 tabs 40 tabs 60 tabs 80 tabs 100tabs 0 0 0 0 0 0 0 0 0 0 0 0 0 1 90 61 0 0 0 0 0 0 0 0 0 0 2 88 91 0 0 00 0 0 0 0 0 0 3 90 92 0 0 0 0 0 0 0 0 0 0 4 90 92 1 0 0 0 0 0 0 0 0 0 589 92 2 1 0 0 0 0 0 0 0 0 6 88 91 3 2 0 0 0 0 0 0 0 0 22 86 90 22 17 0 017 11 10 1 1 1.2 23 87 90 22 18 0 0 18 12 10 1.2 1.2 1.4 24 90 90 22 190 0 18 13 10 1.5 1.4 1.7 Starting pH 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.02.0 2.0 2.0 Ending pH 2.5 8.01 9.08 9.11 9.19 9.28 9.24 9.24 9.26 9.279.26 9.24

Example 6. Preparation of Oxycodone HCl Overdose Resistant (ODR) 5 mgTablets

Formula for Core Ingredients % w/w Oxycodone HCl 2.50 Lactose 68.50Crospovidone 2.00 Microcrystalline cellulose 15.00 Starch 1500 10.00Stearic Acid 2.00

Formula for the Acid Labile Coat* Ingredients % w/w Eudragit E 9.73Sodium Lauryl Sulfate 0.97 Talc 3.40 Stearic Acid 1.46 SimethiconeEmulsion 30% 2.81 Water 81.63 *1375.64 g of coating suspension was madeand applied to 500 g of tablets

Formula for Alkalinizing Coat* Ingredients % w/w Opadry White 10.00Magnesium Hydroxide 20.18 Water 69.82 *1000 g of coating suspension wasmade and applied to 500 g of tablets

Processing Techniques

Step 1a. Preparation of Granules for the Core:

All the ingredients with the exception of the stearic acid from the coreformula were charged into a high shear granulator and dry mixed for lessthan 10 minutes. The dry mixed granules were discharged into a PatersonKelly V-Blender. The stearic acid was then added to the V-Blender. Thegranules were blended for less than 10 minutes.

Step 1b. Preparation of the Core (Immediate Release Tablets):

The cores are tablets made from the granules prepared in Step 1a. Arotary press was set-up to produce capsule shaped tablets each weighingabout 200 mg (a Manesty tablet press with 16 stations was used).Granules from Step 1a were charged into a feed hopper and the tablet wasproduced from the double rotary press by applying suitable compressionforce to give tablets of required thickness, hardness and friability.

Step 2. Preparation of a Coating Suspension of the Ingredients of theAcid Labile Coat:

(I) Water was added into a stainless steel vessel followed by sodiumlauryl sulfate until dissolved. To this was added stearic acid followedby Eudragit E and talc, step-by-step, while stirring vigorously with ahigh shear mixer until all ingredients were finely dispersed in asuspension. (II) Simethicone emulsion was added to the Eudragit Esuspension while stirring using a high shear mixer.

Step 3. Application of the Coating Suspension from Step 2 to Form anAcid Labile Coat Surrounding the Tablet from Step 1b:

Tablets from Step 1b were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 2 was applied to thetablets obtained from Step 1b, using a peristaltic pump and spray gun.The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to form about 40 mg/cm² to about 50 mg/cm² ofthe coat surrounding the tablet.

Step 4. Preparation of a Coating Suspension of the Ingredients of theAlkalinizing Coat:

(I) Water was added into a stainless steel vessel followed by OpadryWhite until no lumps are seen in the resulting suspension. (II) To avortex of this suspension was added magnesium hydroxide until finelydispersed.

Step 5. Application of the Coating Suspension from Step 4 to Form anAlkalinizing Coat Surrounding the Coated Tablet from Step 3:

Tablets from Step 3 were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 4 was applied to thetablets obtained from Step 3, using a peristaltic pump and spray gun.The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to a weight gain of about 50% wt/wt to about70% wt/wt of the coated tablet from Step 3.

Example 7. Dissolution Test of Coated Tablets from Example 6

Tablets from Example 6 were placed into 500 ml of a 0.01 N HCl solutionand were agitated with paddles at 100 rpm for various times at 37° C.Table 15 and corresponding FIGS. 15A and 15B show that increasingnumbers of tablets in the solution led to decreased dissolution of thetablets, both in terms of time and extent of total dissolution. FIGS.15C and 15D show images of 1 and 2 tablets, respectively, dissolvingcompletely after 1 hour. FIGS. 15E, 15F, 15G, 15H, 15I, 15J, and 15Kshow images of the 3-50 tablet experiments, respectively, with thetablets remaining intact (other than the alkalinizing coat) after 24hours.

The thicker acid labile coating on these tablets as compared to those ofExamples 2 and 4 appears to have protected them from the mechanicaldisintegration caused by the paddles and other tablets hitting oneanother, as even after 100 tablets have been mixed for 24 hours, therewas no dissolution of the tablets.

TABLE 15 Comparative dissolution of different quantities of tablets madeaccording to Example 2 in 500 ml 0.01N HCl (pH 2.0). Number of tabletsin dissolution vessel and percent dissolved Time (hrs) 1 tab 2 tabs 3tabs 4 tabs 5 tabs 6 tabs 10 tabs 20 tabs 40 tabs 60 tabs 80 tabs 100tabs 0 0 0 0 0 0 0 0 0 0 0 0 0 1 83 3 0 0 0 0 0 0 0 0 0 0 2 92 4 0 0 0 00 0 0 0 0 0 3 93 4 0 0 0 0 0 0 0 0 0 0 4 92 4 0 0 0 0 0 0 0 0 0 0 5 91 40 0 0 0 0 0 0 0 0 0 6 91 4 0 0 0 0 0 0 0 0 0 0 22 92 16 0 0 0 0 0 0 0 00 0 23 91 18 0 0 0 0 0 0 0 0 0 0 24 91 19 0 0 0 0 0 0 0 0 0 0 StartingpH 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 Ending pH 2.86 9.079.20 9.27 9.28 9.26 9.19 9.25 9.28 9.25 9.24 9.25

Tablets from Example 6 were next placed into 300 ml of a 0.1 N HClsolution with a pH of 1.0 and were agitated with paddles at 100 rpm forvarious times at 37° C. FIG. 15L shows that increasing numbers oftablets in the solution led to decreased dissolution of the tablets,both in terms of time and extent of total dissolution, as measured byHPLC.

Tablets from Example 6 were next placed into 500 ml of a 0.1 N HClsolution with a pH of 1.0 and were agitated with paddles at 100 rpm forvarious times at 37° C. FIG. 15M shows that increasing numbers oftablets in the solution led to decreased dissolution of the tablets,both in terms of time and extent of total dissolution, as measured byHPLC.

Example 8. Comparative Dissolution Test of Coated Tablets from Examples2, 4, and 6

One hundred tablets from each of Examples 2, 4, and 6 were placed into900 ml of a 0.1 N HCl solution with a pH of 1.0 and were agitated withpaddles at 100 rpm for various times at 37° C. HPLC measurements weretaken at each time point to determine how much of the oxycodone wasreleased. The results are shown in FIGS. 16A and 16B, where it isevident that the tablets of Example 6 showed the lowest release,followed by the tablets of Example 4, then Example 2.

Example 9. Oxycodone HCl+Acetaminophen Overdose Resistant (ODR) 5/325 mgTablets

Formula for Core Ingredients % w/w Oxycodone HCl 1.00 Acetaminophen65.00 Crospovidone 5.00 Silicone dioxide 1.00 Microcrystalline cellulose16.00 Starch 1500 10.00 Stearic Acid 2.00

Formula for Acid Labile Coat* Ingredients % w/w Eudragit E 9.73 SodiumLauryl Sulfate 0.97 Talc 3.40 Stearic Acid 1.46 Simethicone Emulsion 30%2.81 Water 81.63 *687.82 g of coating suspension was made and applied to500 g of tablets

Formula for Alkalinizing layer (coat) Ingredients % w/w Opadry White10.00 Magnesium Hydroxide 20.18 Water 69.82 *1000 g of coatingsuspension was made and applied to 500 g of tablets

Processing Techniques

Step 1a. Preparation of Granules for the Core:

All the ingredients with the exception of the stearic acid from the coreformula were charged into a high shear granulator and dry mixed for lessthan 10 minutes. The dry mixed granules were discharged into a PatersonKelly V-Blender. The stearic acid was then added to the V-Blender. Thegranules were blended for less than 10 minutes.

Step 1b. Preparation of the Core (Immediate Release Tablets):

The cores are tablets made from the granules prepared in Step 1a. Arotary press was set-up to produce capsule shaped tablets each weighingabout 500 mg (a Manesty tablet press with 16 stations was used).Granules from Step 1a were charged into a feed hopper and the tablet wasproduced from the double rotary press by applying suitable compressionforce to give tablets of required thickness, hardness and friability.

Step 2. Preparation of a Coating Suspension of the Ingredients of theAcid Labile Coat:

(I) Water was added into a stainless steel vessel followed by sodiumlauryl sulfate until dissolved. To this was added stearic acid followedby Eudragit E and talc, step-by-step, while stirring vigorously with ahigh shear mixer until all ingredients were finely dispersed in asuspension. (II) Simethicone emulsion was added to the Eudragit Esuspension while stirring using a high shear mixer.

Step 3. Application of the Coating Suspension from Step 2 to Form anAcid Labile Coat Surrounding the Tablet from Step 1b:

Tablets from Step 1b were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 2 was applied to thetablets obtained from Step 1b, using a peristaltic pump and spray gun.The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to form about 19 mg/cm² to about 25 mg/cm² ofthe coat surrounding the tablet.

Step 4. Preparation of a Coating Suspension of the Ingredients of theAlkalinizing Coat:

(I) Water was added into a stainless steel vessel followed by OpadryWhite until no lumps are seen in the resulting suspension. (II) To avortex of this suspension was added magnesium hydroxide until finelydispersed.

Step 5. Application of the Coating Suspension from Step 4 to Form anAlkalinizing Coat Surrounding the Coated Tablet from Step 3:

Tablets from Step 3 were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 4 was applied to thetablets obtained from Step 3, using a peristaltic pump and spray gun.The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to a weight gain of about 50% wt/wt to about70% wt/wt of the coated tablet from Step 3.

Example 10. Oxycodone HCl+Aspirin Overdose Resistant (ODR) 5/325 mgTablets

Formula for Core Ingredients % w/w Oxycodone HCl 1.25 Aspirin USP 81.25Microcrystalline cellulose 15.50 Stearic Acid 2.00

Formula for Acid Labile Coat* Ingredients % w/w Eudragit E 9.73 SodiumLauryl Sulfate 0.97 Talc 3.40 Stearic Acid 1.46 Simethicone Emulsion 30%2.81 Water 81.63 *687.82 g of coating suspension was made and applied to500 g of tablets

Formula for Alkalinizing Coat* Ingredients % w/w Opadry White 10.00Magnesium Hydroxide 20.18 Water 69.82 *1000 g of coating suspension wasmade and applied to 500 g of tablets

Processing Techniques

Step 1a. Preparation of Granules for the Core:

All the ingredients with the exception of the stearic acid from the coreformula were charged into a high shear granulator and dry mixed for lessthan 10 minutes. The dry mixed granules were discharged into a PatersonKelly V-Blender. The stearic acid was then added to the V-Blender. Thegranules were blended for less than 10 minutes.

Step 1b. Preparation of the Core (Immediate Release Tablets):

The cores are tablets made from the granules prepared in Step 1a. Arotary press was set-up to produce capsule shaped tablets each weighingabout 400 mg (a Manesty tablet press with 16 stations was used).Granules from Step 1a were charged into a feed hopper and the tablet wasproduced from the double rotary press by applying suitable compressionforce to give tablets of required thickness, hardness and friability.

Step 2. Preparation of a Coating Suspension of the Ingredients of theAcid Labile Coat:

(I) Water was added into a stainless steel vessel followed by sodiumlauryl sulfate until dissolved. To this was added stearic acid followedby Eudragit E and talc, step-by-step, while stirring vigorously with ahigh shear mixer until all ingredients were finely dispersed in asuspension. (II) Simethicone emulsion was added to the Eudragit Esuspension while stirring using a high shear mixer.

Step 3. Application of the Coating Suspension from Step 2 to Form anAcid Labile Coat Surrounding the Tablet from Step 1b:

Tablets from Step 1b were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 2 was applied to thetablets obtained from Step 1b, using a peristaltic pump and spray gun.The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to form about 19 mg/cm² to about 25 mg/cm² ofthe coat surrounding the tablet.

Step 4. Preparation of a Coating Suspension of the Ingredients of theAlkalinizing Coat:

(I) Water was added into a stainless steel vessel followed by OpadryWhite until no lumps are seen in the resulting suspension. (II) To avortex of this suspension was added magnesium hydroxide until finelydispersed.

Step 5. Application of the Coating Suspension from Step 4 to Form anAlkalinizing Coat Surrounding the Coated Tablet from Step 3:

Tablets from Step 3 were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 4 was applied to thetablets obtained from Step 3, using a peristaltic pump and spray gun.The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to a weight gain of about 50% wt/wt to about70% wt/wt of the coated tablet from Step 3.

Example 11. Oxycodone HCl+Ibuprophen Overdose Resistant (ODR) 5/400 mgTablets

Formula for Core Ingredients % w/w Oxycodone HCl USP 0.83 Ibuprofen USP66.67 Crospovidone 4.00 Silicone dioxide 1.00 Microcrystalline cellulose15.33 Povidone K90 2.00 Starch 1500 7.17 Stearic Acid 1.50 Calciumstearate 1.50

Formula for Acid Labile Coat* Ingredients % w/w Eudragit E 9.73 SodiumLauryl Sulfate 0.97 Talc 3.40 Stearic Acid 1.46 Simethicone Emulsion 30%2.81 Water 81.63 *687.82 g of coating suspension was made and applied to500 g of tablets

Formula for Alkalinizing Coat* Ingredients % w/w Opadry White 10.00Magnesium Hydroxide 20.18 Water 69.82 *1000 g of coating suspension wasmade and applied to 500 g of tablets

Processing Techniques

Step 1a. Preparation of Granules for the Core:

All the ingredients with the exception of povidone, stearic acid and thecalcium stearate from the core formula were charged into a high sheargranulator and dry mixed for less than 10 minutes. The dry mixedgranules were granulated using a 10% povidone solution. The wet granuleswere dried in an oven at 60° C. to a loss of drying of less than 2%. Thedried granules were passed through a co-mill fitted with screen sieveswith holes of size 1000 microns and discharged into a Paterson KellyV-Blender. The stearic acid and calcium stearate was then added to theV-Blender. The granules were blended for less than 10 minutes.

Step 1b. Preparation of the Core (Immediate Release Tablets):

The cores are tablets made from the granules prepared in Step 1a. Arotary press was set-up to produce capsule shaped tablets each weighingabout 600 mg (a Manesty tablet press with 16 stations was used).Granules from Step 1a were charged into a feed hopper and the tablet wasproduced from the double rotary press by applying suitable compressionforce to give tablets of required thickness, hardness and friability.

Step 2. Preparation of a Coating Suspension of the Ingredients of theAcid Labile Coat:

(I) Water was added into a stainless steel vessel followed by sodiumlauryl sulfate until dissolved. To this was added stearic acid followedby Eudragit E and talc, step-by-step, while stirring vigorously with ahigh shear mixer until all ingredients were finely dispersed in asuspension. (II) Simethicone emulsion was added to the Eudragit Esuspension while stirring using a high shear mixer.

Step 3. Application of the Coating Suspension from Step 2 to Form anAcid Labile Coat Surrounding the Tablet from Step 1b:

Tablets from Step 1b were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 2 was applied to thetablets obtained from Step 1b, using a peristaltic pump and spray gun.The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to form about 19 mg/cm² to about 25 mg/cm² ofthe coat surrounding the tablet.

Step 4. Preparation of a Coating Suspension of the Ingredients of theAlkalinizing Coat:

(I) Water was added into a stainless steel vessel followed by OpadryWhite until no lumps are seen in the resulting suspension. (II) To avortex of this suspension was added magnesium hydroxide until finelydispersed.

Step 5. Application of the Coating Suspension from Step 4 to Form anAlkalinizing Coat Surrounding the Coated Tablet from Step 3:

Tablets from Step 3 were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 4 was applied to thetablets obtained from Step 3, using a peristaltic pump and spray gun.The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to a weight gain of about 50% wt/wt to about70% wt/wt of the coated tablet from Step 3.

Example 12. Diazepam Overdose Resistant (ODR) 5 mg Tablets

Formula for Core Ingredients % w/w Diazepam 2.50 Lactose 70.00Microcrystalline cellulose 15.00 Starch 1500 10.00 Calcium stearate 2.50

Formula for Acid Labile Coat* Ingredients % w/w Eudragit E 9.73 SodiumLauryl Sulfate 0.97 Talc 3.40 Stearic Acid 1.46 Simethicone Emulsion 30%2.81 Water 81.63 *345 g of coating suspension was made and applied to500 g of tablets

Formula for Alkalinizing Coat* Ingredients % w/w Opadry White 10.00Magnesium Hydroxide 20.18 Water 69.82 *1000 g of coating suspension wasmade and applied to 500 g of tablets

Processing Techniques

Step 1a. Preparation of Granules for the Core:

All the ingredients with the exception of the calcium stearate from thecore formula were charged into a high shear granulator and dry mixed forless than 10 minutes. The dry mixed granules were discharged into aPaterson Kelly V-Blender. The calcium stearate was then added to theV-Blender. The granules were blended for less than 10 minutes.

Step 1b. Preparation of the Core (Immediate Release Tablets):

The cores are tablets made from the granules prepared in Step 1a. Arotary press was set-up to produce capsule shaped tablets each weighingabout 200 mg (a Manesty tablet press with 16 stations was used).Granules from Step 1a were charged into a feed hopper and the tablet wasproduced from the double rotary press by applying suitable compressionforce to give tablets of required thickness, hardness and friability.

Step 2. Preparation of a Coating Suspension of the Ingredients of theAcid Labile Coat:

(I) Water was added into a stainless steel vessel followed by sodiumlauryl sulfate until dissolved. To this was added stearic acid followedby Eudragit E and talc, step-by-step, while stirring vigorously with ahigh shear mixer until all ingredients were finely dispersed in asuspension. (II) Simethicone emulsion was added to the Eudragit Esuspension while stirring using a high shear mixer.

Step 3. Application of the Coating Suspension from Step 2 to Form anAcid Labile Coat Surrounding the Tablet from Step 1b:

Tablets from Step 1b were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 2 was applied to thetablets obtained from Step 1b, using a peristaltic pump and spray gun.The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to form about 8 mg/cm² to about 12 mg/cm² ofthe coat surrounding the tablet.

Step 4. Preparation of a Coating Suspension of the Ingredients of theAlkalinizing Coat:

(I) Water was added into a stainless steel vessel followed by OpadryWhite until no lumps are seen in the resulting suspension. (II) To avortex of this suspension was added magnesium hydroxide until finelydispersed.

Step 5. Application of the Coating Suspension from Step 4 to Form anAlkalinizing Coat Surrounding the Coated Tablet from Step 3:

Tablets from Step 3 were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 4 was applied to thetablets obtained from Step 3, using a peristaltic pump and spray gun.The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to a weight gain of about 50% wt/wt to about70% wt/wt of the coated tablet from Step 3.

Example 13. Phenobarbital Overdose Resistant (ODR) 30 mg Tablets

Formula for Core Ingredients % w/w Phenobarbital 7.50 Lactose 66.00Microcrystalline cellulose 15.00 Starch 1500 10.00 Magnesium stearate1.50

Formula for Acid Labile Coat* Ingredients % w/w Eudragit E 9.73 SodiumLauryl Sulfate 0.97 Talc 3.40 Stearic Acid 1.46 Simethicone Emulsion 30%2.81 Water 81.63 *345 g of coating suspension was made and applied to500 g of tablets

Formula for Alkalinizing Coat* Ingredients % w/w Opadry White 10.00Magnesium Hydroxide 20.18 Water 69.82 *1000 g of coating suspension wasmade and applied to 500 g of tablets

Processing Techniques

Step 1a. Preparation of Granules for the Core:

All the ingredients with the exception of the magnesium stearate fromthe core formula were charged into a high shear granulator and dry mixedfor less than 10 minutes. The dry mixed granules were discharged into aPaterson Kelly V-Blender. The magnesium stearate was then added to theV-Blender. The granules were blended for less than 10 minutes.

Step 1b. Preparation of the Core (Immediate Release Tablets):

The cores are tablets made from the granules prepared in Step 1a. Arotary press was set-up to produce capsule shaped tablets each weighingabout 400 mg (a Manesty tablet press with 16 stations was used).Granules from Step 1a were charged into a feed hopper and the tablet wasproduced from the double rotary press by applying suitable compressionforce to give tablets of required thickness, hardness and friability.

Step 2. Preparation of a Coating Suspension of the Ingredients of theAcid Labile Coat:

(I) Water was added into a stainless steel vessel followed by sodiumlauryl sulfate until dissolved. To this was added stearic acid followedby Eudragit E and talc, step-by-step, while stirring vigorously with ahigh shear mixer until all ingredients were finely dispersed in asuspension. (II) Simethicone emulsion was added to the Eudragit Esuspension while stirring using a high shear mixer.

Step 3. Application of the Coating Suspension from Step 2 to Form anAcid Labile Coat Surrounding the Tablet from Step 1b:

Tablets from Step 1b were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 2 was applied to thetablets obtained from Step 1b, using a peristaltic pump and spray gun.The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to form about 8 mg/cm² to about 12 mg/cm² ofthe coat surrounding the tablet.

Step 4. Preparation of a Coating Suspension of the Ingredients of theAlkalinizing Coat:

(I) Water was added into a stainless steel vessel followed by OpadryWhite until no lumps are seen in the resulting suspension. (II) To avortex of this suspension was added magnesium hydroxide until finelydispersed.

Step 5. Application of the Coating Suspension from Step 4 to Form anAlkalinizing Coat Surrounding the Coated Tablet from Step 3:

Tablets from Step 3 were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 4 was applied to thetablets obtained from Step 3, using a peristaltic pump and spray gun.The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to a weight gain of about 50% wt/wt to about70% wt/wt of the coated tablet from Step 3.

Example 14. Oxycodone HCl Overdose+Insufflation Resistant (ODIR) 5 mgTablets

Formula for Core Ingredients % w/w Oxycodone HCl 1.67 Lactose 38.50Sodium Lauryl Sulfate 26.66 Capsaicin 3.00 Crospovidone 2.00Microcrystalline cellulose 16.17 Starch 1500 10.00 Stearic Acid 2.00

Formula for Acid Labile Coat* Ingredients % w/w Eudragit E 9.73 SodiumLauryl Sulfate 0.97 Talc 3.40 Stearic Acid 1.46 Simethicone Emulsion 30%2.81 Water 81.63 *1375.64 g of coating suspension was made and appliedto 500 g of tablets

Formula for Alkalinizing Coat* Ingredients % w/w Opadry White 10.00Magnesium Hydroxide 20.18 Water 69.82 *1000 g of coating suspension wasmade and applied to 500 g of tablets

Processing Techniques

Step 1a. Preparation of Granules for the Core:

All the ingredients with the exception of the stearic acid from the coreformula were charged into a high shear granulator and dry mixed for lessthan 10 minutes. The dry mixed granules were discharged into a PatersonKelly V-Blender. The stearic acid was then added to the V-Blender. Thegranules were blended for less than 10 minutes.

Step 1b. Preparation of the Core (Immediate Release Tablets):

The cores are tablets made from the granules prepared in Step 1a. Arotary press was set-up to produce capsule shaped tablets each weighingabout 300 mg (a Manesty tablet press with 16 stations was used).Granules from Step 1a were charged into a feed hopper and the tablet wasproduced from the double rotary press by applying suitable compressionforce to give tablets of required thickness, hardness and friability.

Step 2. Preparation of a Coating Suspension of the Ingredients of theAcid Labile (Coat):

(I) Water was added into a stainless steel vessel followed by sodiumlauryl sulfate until dissolved. To this was added stearic acid followedby Eudragit E and talc, step-by-step, while stirring vigorously with ahigh shear mixer until all ingredients were finely dispersed in asuspension. (II) Simethicone emulsion was added to the Eudragit Esuspension while stirring using a high shear mixer.

Step 3. Application of the Coating Suspension from Step 2 to Form anAcid Labile Coat Surrounding the Tablet from Step 1b:

Tablets from Step 1b were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 2 was applied to thetablets obtained from Step 1b, using a peristaltic pump and spray gun.The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to form about 40 mg/cm² to about 50 mg/cm² ofthe coat surrounding the tablet.

Step 4. Preparation of a Coating Suspension of the Ingredients of theAlkalinizing Coat:

(I) Water was added into a stainless steel vessel followed by OpadryWhite until no lumps are seen in the resulting suspension. (II) To avortex of this suspension was added magnesium hydroxide until finelydispersed.

Step 5. Application of the Coating Suspension from Step 4 to Form anAlkalinizing Coat Surrounding the Coated Tablet from Step 3:

Tablets from Step 3 were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 4 was applied to thetablets obtained from Step 3, using a peristaltic pump and spray gun.The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to a weight gain of about 50% wt/wt to about70% wt/wt of the coated tablet from Step 3.

Example 15. Hydromorphone HCl Overdose+Insufflation Resistant (ODIR) 8mg Tablets

Formula for Core Ingredients % w/w Hydromorphone HCl 2.67 Lactose 46.50Sodium Lauryl Sulfate 16.00 Citric acid 10.00 Capsicum Oleoresin 1.17Crospovidone 2.00 Microcrystalline cellulose 15.66 Starch 1500 5.00Magnesium stearate 1.00

Formula for the Acid Labile Coat* Ingredients % w/w Eudragit E 9.73Sodium Lauryl Sulfate 0.97 Talc 3.40 Stearic Acid 1.46 SimethiconeEmulsion 30% 2.81 Water 81.63 *1375.64 g of coating suspension was madeand applied to 500 g of tablets

Formula for Alkalinizing Coat Ingredients % w/w Opadry White 10.00Magnesium Hydroxide 20.18 Water 69.82 *1000 g of coating suspension wasmade and applied to 500 g of tablets

Processing Techniques

Step 1a. Preparation of Granules for the Core:

All the ingredients with the exception of the magnesium stearate fromthe core formula were charged into a high shear granulator and dry mixedfor less than 10 minutes. The dry mixed granules were discharged into aPaterson Kelly V-Blender. The magnesium stearate was then added to theV-Blender. The granules were blended for less than 10 minutes.

Step 1b. Preparation of the Core (Immediate Release Tablets):

The cores are tablets made from the granules prepared in Step 1a. Arotary press was set-up to produce capsule shaped tablets each weighingabout 300 mg (a Manesty tablet press with 16 stations was used).Granules from Step 1a were charged into a feed hopper and the tablet wasproduced from the double rotary press by applying suitable compressionforce to give tablets of required thickness, hardness and friability.

Step 2. Preparation of a Coating Suspension of the Ingredients of theAcid Labile Coat:

(I) Water was added into a stainless steel vessel followed by sodiumlauryl sulfate until dissolved. To this was added stearic acid followedby Eudragit E and talc, step-by-step, while stirring vigorously with ahigh shear mixer until all ingredients were finely dispersed in asuspension. (II) Simethicone emulsion was added to the Eudragit Esuspension while stirring using a high shear mixer.

Step 3. Application of the Coating Suspension from Step 2 to Form anAcid Labile Coat Surrounding the Tablet from Step 1b:

Tablets from Step 1b were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 2 was applied to thetablets obtained from Step 1b, using a peristaltic pump and spray gun.The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to form about 40 mg/cm² to about 50 mg/cm² ofthe coat surrounding the tablet.

Step 4. Preparation of a Coating Suspension of the Ingredients of theAlkalinizing Coat:

(I) Water was added into a stainless steel vessel followed by OpadryWhite until no lumps are seen in the resulting suspension. (II) To avortex of this suspension was added magnesium hydroxide until finelydispersed.

Step 5. Application of the Coating Suspension from Step 4 to Form anAlkalinizing Coat Surrounding the Coated Tablet from Step 3:

Tablets from Step 3 were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 4 was applied to thetablets obtained from Step 3, using a peristaltic pump and spray gun.The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to a weight gain of about 50% wt/wt to about70% wt/wt of the coated tablet from Step 3.

Example 16. Hydrocodone Bitartrate/Acetamenophen Overdose+InsufflationResistant (ODIR) 5/500 mg Tablets

Formula for Core Ingredients % w/w Hydrocodone Bitartrate 0.63Acetaminophen 62.50 Crospovidone 4.00 Capsaicin 1.50 Citric acid 12.50Silicon dioxide 1.00 Microcrystalline cellulose 13.37 Povidone K90 2.00Stearic Acid 1.50 Magnesium stearate 1.00 100

Formula for the Acid Labile Coat* Ingredients % w/w Eudragit E 9.73Sodium Lauryl Sulfate 0.97 Talc 3.40 Stearic Acid 1.46 SimethiconeEmulsion 30% 2.81 Water 81.63 *687.82 g of coating suspension was madeand applied to 500 g of tablets

Formula for Alkalinizing Coat* Ingredients % w/w Opadry White 10.00Magnesium Hydroxide 20.18 Water 69.82 *1000 g of coating suspension wasmade and applied to 500 g of tablets

Processing Techniques

Step 1a. Preparation of Granules for the Core:

All the ingredients with the exception of povidone, stearic acid and themagnesium stearate from the core formula were charged into a high sheargranulator and dry mixed for less than 10 minutes. The dry mixedgranules were granulated using a 10% povidone solution. The wet granuleswere dried in an oven at 60° C. to a loss of drying of less than 2%. Thedried granules were passed through a co-mill fitted with screen sieveswith holes of size 1000 microns and discharged into a Paterson KellyV-Blender. The stearic acid and magnesium stearate was then added to theV-Blender. The granules were blended for less than 10 minutes.

Step 1b. Preparation of the Core (Immediate Release Tablets):

The cores are tablets made from the granules prepared in Step 1a. Arotary press was set-up to produce capsule shaped tablets each weighingabout 800 mg (a Manesty tablet press with 16 stations was used).Granules from Step 1a were charged into a feed hopper and the tablet wasproduced from the double rotary press by applying suitable compressionforce to give tablets of required thickness, hardness and friability.

Step 2. Preparation of a Coating Suspension of the Ingredients of theAcid Labile Coat:

(I) Water was added into a stainless steel vessel followed by sodiumlauryl sulfate until dissolved. To this was added stearic acid followedby Eudragit E and talc, step-by-step, while stirring vigorously with ahigh shear mixer until all ingredients were finely dispersed in asuspension. (II) Simethicone emulsion was added to the Eudragit Esuspension while stirring using a high shear mixer.

Step 3. Application of the Coating Suspension from Step 2 to Form anAcid Labile Coat Surrounding the Tablet from Step 1b:

Tablets from Step 1b were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 2 was applied to thetablets obtained from Step 1b, using a peristaltic pump and spray gun.The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to form about 40 mg/cm² to about 50 mg/cm² ofthe coat surrounding the tablet.

Step 4. Preparation of a Coating Suspension of the Ingredients of theAlkalinizing Coat:

(I) Water was added into a stainless steel vessel followed by OpadryWhite until no lumps are seen in the resulting suspension. (II) To avortex of this suspension was added magnesium hydroxide until finelydispersed.

Step 5. Application of the Coating Suspension from Step 4 to Form anAlkalinizing Coat Surrounding the Coated Tablet from Step 3:

Tablets from Step 3 were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 4 was applied to thetablets obtained from Step 3, using a peristaltic pump and spray gun.The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to a weight gain of about 50% wt/wt to about70% wt/wt of the coated tablet from Step 3.

Example 17. Oxycodone HCl Overdose+Insufflation Resistant (ODIR) 5 mg

Tablets

Formula for Core Ingredients % w/w Oxycodone HCl 1.67 Lactose 40.67Sodium Lauryl Sulfate 20.16 Sucrose Octa Acetate 0.50 Capsaicin 3.00Crospovidone 2.00 Microcrystalline cellulose 20.00 Starch 1500 10.00Stearic Acid 2.00

Formula for Acid Labile Coat* Ingredients % w/w Eudragit E 9.73 SodiumLauryl Sulfate 0.97 Talc 3.40 Stearic Acid 1.46 Simethicone Emulsion 30%2.81 Water 81.63 *1375.64 g of coating suspension was made and appliedto 500 g of tablets

Formula for Alkalinizing Coat* Ingredients % w/w Opadry White 10.00Magnesium Hydroxide 20.18 Water 69.82 *1000 g of coating suspension wasmade and applied to 500 g of tablets

Processing Techniques

Step 1a. Preparation of Granules for the Core:

All the ingredients with the exception of the stearic acid from the coreformula were charged into a high shear granulator and dry mixed for lessthan 10 minutes. The dry mixed granules were discharged into a PatersonKelly V-Blender. The stearic acid was then added to the V-Blender. Thegranules were blended for less than 10 minutes.

Step 1b. Preparation of the Core (Immediate Release Tablets):

The cores are tablets made from the granules prepared in Step 1a. Arotary press was set-up to produce capsule shaped tablets each weighingabout 300 mg (a Manesty tablet press with 16 stations was used).Granules from Step 1a were charged into a feed hopper and the tablet wasproduced from the double rotary press by applying suitable compressionforce to give tablets of required thickness, hardness and friability.

Step 2. Preparation of a Coating Suspension of the Ingredients of theAcid Labile Coat:

(I) Water was added into a stainless steel vessel followed by sodiumlauryl sulfate until dissolved. To this was added stearic acid followedby Eudragit E and talc, step-by-step, while stirring vigorously with ahigh shear mixer until all ingredients were finely dispersed in asuspension. (II) Simethicone emulsion was added to the Eudragit Esuspension while stirring using a high shear mixer.

Step 3. Application of the Coating Suspension from Step 2 to Form anAcid Labile Coat Surrounding the Tablet from Step 1b:

Tablets from Step 1b were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 2 was applied to thetablets obtained from Step 1b, using a peristaltic pump and spray gun.The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to form about 40 mg/cm² to about 50 mg/cm² ofthe coat surrounding the tablet.

Step 4. Preparation of a Coating Suspension of the Ingredients of theAlkalinizing Coat:

(I) Water was added into a stainless steel vessel followed by OpadryWhite until no lumps are seen in the resulting suspension. (II) To avortex of this suspension was added magnesium hydroxide until finelydispersed.

Step 5. Application of the Coating Suspension from Step 4 to Form anAlkalinizing Coat Surrounding the Coated Tablet from Step 3:

Tablets from Step 3 were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 4 was applied to thetablets obtained from Step 3, using a peristaltic pump and spray gun.The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to a weight gain of about 50% wt/wt to about70% wt/wt of the coated tablet from Step 3.

Example 18. Oxymorphone HCl Overdose+Insufflation Resistant (ODIR) 10 mgTablets

Formula for Core Ingredients % w/w Oxymorphone HCl 10.00 Lactose 35.00Sodium Lauryl Sulfate 19.33 Quassin 1.50 Citric acid 10.00 CapsicumOleoresin 1.17 Crospovidone 2.00 Microcrystalline cellulose 15.00 Starch1500 5.00 Magnesium stearate 1.00 100

Formula for Acid Labile Coat* Ingredients % w/w Eudragit E 9.73 SodiumLauryl Sulfate 0.97 Talc 3.40 Stearic Acid 1.46 Simethicone Emulsion 30%2.81 Water 81.63 *1375.64 g of coating suspension was made and appliedto 500 g of tablets

Formula for Alkalinizing Coat* Ingredients % w/w Opadry White 10.00Magnesium Hydroxide 20.18 Water 69.82 *1000 g of coating suspension wasmade and applied to 500 g of tablets

Processing Techniques

Step 1a. Preparation of Granules for the Core:

All the ingredients with the exception of the magnesium stearate fromthe core formula were charged into a high shear granulator and dry mixedfor less than 10 minutes. The dry mixed granules were discharged into aPaterson Kelly V-Blender. The magnesium stearate was then added to theV-Blender. The granules were blended for less than 10 minutes.

Step 1b. Preparation of the core (immediate release tablets):

The cores are tablets made from the granules prepared in Step 1a. Arotary press was set-up to produce capsule shaped tablets each weighingabout 300 mg (a Manesty tablet press with 16 stations was used).Granules from Step 1a were charged into a feed hopper and the tablet wasproduced from the double rotary press by applying suitable compressionforce to give tablets of required thickness, hardness and friability.

Step 2. Preparation of a Coating Suspension of the Ingredients of theAcid Labile Coat:

(I) Water was added into a stainless steel vessel followed by sodiumlauryl sulfate until dissolved. To this was added stearic acid followedby Eudragit E and talc, step-by-step, while stirring vigorously with ahigh shear mixer until all ingredients were finely dispersed in asuspension. (II) Simethicone emulsion was added to the Eudragit Esuspension while stirring using a high shear mixer.

Step 3. Application of the Coating Suspension from Step 2 to Form anAcid Labile Coat Surrounding the Tablet from Step 1b:

Tablets from Step 1b were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 2 was applied to thetablets obtained from Step 1b, using a peristaltic pump and spray gun.The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to form about 40 mg/cm² to about 50 mg/cm² ofthe coat surrounding the tablet.

Step 4. Preparation of a Coating Suspension of the Ingredients of theAlkalinizing Coat:

(I) Water was added into a stainless steel vessel followed by OpadryWhite until no lumps are seen in the resulting suspension. (II) To avortex of this suspension was added magnesium hydroxide until finelydispersed.

Step 5. Application of the Coating Suspension from Step 4 to Form anAlkalanizing Coat Surrounding the Coated Tablet from Step 3:

Tablets from Step 3 were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 4 was applied to thetablets obtained from Step 3, using a peristaltic pump and spray gun.The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to a weight gain of about 50% wt/wt to about70% wt/wt of the coated tablet from Step 3.

Example 19. Warfarin Sodium Overdose Resistant (ODR) 10 mg Tablets

Formula for Core Ingredients % w/w Warfarin sodium 5.00 Lactose 84.00Starch 1500 10.00 Magnesium stearate 1.00

Formula for Acid Labile Coat* Ingredients % w/w Eudragit E 9.73 SodiumLauryl Sulfate 0.97 Talc 3.40 Stearic Acid 1.46 Simethicone Emulsion 30%2.81 Water 81.63 *1375.64 g of coating suspension was made and appliedto 500 g of tablets

Formula for Alkalinizing Coat* Ingredients % w/w Opadry White 10.00Magnesium Hydroxide 20.18 Water 69.82 *1000 g of coating suspension wasmade and applied to 500 g of tablets

Processing Techniques

Step 1a. Preparation of Granules for the Core:

All the ingredients with the exception of the magnesium stearate fromthe core formula were charged into a high shear granulator and dry mixedfor less than 10 minutes. The dry mixed granules were discharged into aPaterson Kelly V-Blender. The magnesium stearate was then added to theV-Blender. The granules were blended for less than 10 minutes.

Step 1b. Preparation of the Core (Immediate Release Tablets):

The cores are tablets made from the granules prepared in Step 1a. Arotary press was set-up to produce capsule shaped tablets each weighingabout 200 mg (a Manesty tablet press with 16 stations was used).Granules from Step 1a were charged into a feed hopper and the tablet wasproduced from the double rotary press by applying suitable compressionforce to give tablets of required thickness, hardness and friability.

Step 2. Preparation of a Coating Suspension of the Ingredients of theAcid Labile Coat:

(I) Water was added into a stainless steel vessel followed by sodiumlauryl sulfate until dissolved. To this was added stearic acid followedby Eudragit E and talc, step-by-step, while stirring vigorously with ahigh shear mixer until all ingredients were finely dispersed in asuspension. (II) Simethicone emulsion was added to the Eudragit Esuspension while stirring using a high shear mixer.

Step 3. Application of the Coating Suspension from Step 2 to Form anAcid Labile Coat Surrounding the Tablet from Step 1b:

Tablets from Step 1b were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 2 was applied to thetablets obtained from Step 1b, using a peristaltic pump and spray gun.The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to form about 40 mg/cm² to about 50 mg/cm² ofthe coat surrounding the tablet.

Step 4. Preparation of a Coating Suspension of the Ingredients of theAlkalinizing Coat:

(I) Water was added into a stainless steel vessel followed by OpadryWhite until no lumps are seen in the resulting suspension. (II) To avortex of this suspension was added magnesium hydroxide until finelydispersed.

Step 5. Application of the Coating Suspension from Step 4 to Form anAlkalinizing Coat Surrounding the Coated Tablet from Step 3:

Tablets from Step 3 were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 4 was applied to thetablets obtained from Step 3, using a peristaltic pump and spray gun.The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to a weight gain of about 50% wt/wt to about70% wt/wt of the coated tablet from Step 3.

Example 20. Codeine+Acetaminophen Overdose Resistant (ODR) 30/300 mg

Formula for Core Ingredients % w/w Codeine phosphate 5.00 Acetaminophen50.00 Sodium metabisulfite 0.30 Microcrystalline cellulose 28.20 Starch1500 15.00 Magnesium stearate 1.50

Formula for Acid Labile Coat* Ingredients % w/w Eudragit E 9.73 SodiumLauryl Sulfate 0.97 Talc 3.40 Stearic Acid 1.46 Simethicone Emulsion 30%2.81 Water 81.63 *687.82 g of coating suspension was made and applied to500 g of tablets

Formula for Alkalinizing Coat* Ingredients % w/w Opadry White 10.00Magnesium Hydroxide 20.18 Water 69.82 *1000 g of coating suspension wasmade and applied to 500 g of tablets

Processing Techniques

Step 1a. Preparation of Granules for the Core:

All the ingredients with the exception of magnesium stearate from thecore formula were charged into a high shear granulator and dry mixed forless than 10 minutes. The dry mixed granules were granulated using. Thewet granules were dried in an oven at 60° C. to a loss of drying of lessthan 2%. The dried granules were passed through a co-mill fitted withscreen sieves with holes of size 1000 microns and discharged into aPaterson Kelly V-Blender. The magnesium stearate was then added to theV-Blender. The granules were blended for less than 10 minutes.

Step 1b. Preparation of the Core (Immediate Release Tablets):

The cores are tablets made from the granules prepared in Step 1a. Arotary press was set-up to produce capsule shaped tablets each weighingabout 600 mg (a Manesty tablet press with 16 stations was used).Granules from Step 1a were charged into a feed hopper and the tablet wasproduced from the double rotary press by applying suitable compressionforce to give tablets of required thickness, hardness and friability.

Step 2. Preparation of a Coating Suspension of the Ingredients of theAcid Labile Coat:

(I) Water was added into a stainless steel vessel followed by sodiumlauryl sulfate until dissolved. To this was added stearic acid followedby Eudragit E and talc, step-by-step, while stirring vigorously with ahigh shear mixer until all ingredients were finely dispersed in asuspension. (II) Simethicone emulsion was added to the Eudragit Esuspension while stirring using a high shear mixer.

Step 3. Application of the Coating Suspension from Step 2 to Form anAcid Labile Coat Surrounding the Tablet from Step 1b:

Tablets from Step 1b were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 2 was applied to thetablets obtained from Step 1b, using a peristaltic pump and spray gun.The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to form about 30 mg/cm² to about 40 mg/cm² ofthe coat surrounding the tablet.

Step 4. Preparation of a Coating Suspension of the Ingredients of theAlkalinizing Coat:

(I) Water was added into a stainless steel vessel followed by OpadryWhite until no lumps are seen in the resulting suspension. (II) To avortex of this suspension was added magnesium hydroxide until finelydispersed.

Step 5. Application of the Coating Suspension from Step 4 to Form anAlkalinizing Coat Surrounding the Coated Tablet from Step 3:

Tablets from Step 3 were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 4 was applied to thetablets obtained from Step 3, using a peristaltic pump and spray gun.The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to a weight gain of about 50% wt/wt to about70% wt/wt of the coated tablet from Step 3.

Example 21. Methylphenidate HCl Overdose Resistant (ODR) 10 mg Tablets

Formula for Core Ingredients % w/w Methylphenidate HCl 5.00 Lactose80.00 Hydroxypropyl 4.00 methylcellulose Starch 1500 10.00 Magnesiumstearate 1.00

Formula for Acid Labile Coat* Ingredients % w/w Eudragit E 9.73 SodiumLauryl Sulfate 0.97 Talc 3.40 Stearic Acid 1.46 Simethicone Emulsion 30%2.81 Water 81.63 *1375.64 g of coating suspension was made and appliedto 500 g of tablets

Formula for Alkalinizing Coat* Ingredients % w/w Opadry White 10.00Magnesium Hydroxide 15.18 Aluminium Hydroxide 5.00 Water 69.82 *1000 gof coating suspension was made and applied to 500 g of tablets

Processing Techniques

Step 1a. Preparation of Granules for the Core:

All the ingredients with the exception of the magnesium stearate fromthe core formula were charged into a high shear granulator and dry mixedfor less than 10 minutes. The dry mixed granules were discharged into aPaterson Kelly V-Blender. The magnesium stearate was then added to theV-Blender. The granules were blended for less than 10 minutes.

Step 1b. Preparation of the Core (Immediate Release Tablets):

The cores are tablets made from the granules prepared in Step 1a. Arotary press was set-up to produce capsule shaped tablets each weighingabout 200 mg (a Manesty tablet press with 16 stations was used).Granules from Step 1a were charged into a feed hopper and the tablet wasproduced from the double rotary press by applying suitable compressionforce to give tablets of required thickness, hardness and friability.

Step 2. Preparation of a Coating Suspension of the Ingredients of theAcid Labile Coat:

(I) Water was added into a stainless steel vessel followed by sodiumlauryl sulfate until dissolved. To this was added stearic acid followedby Eudragit E and talc, step-by-step, while stirring vigorously with ahigh shear mixer until all ingredients were finely dispersed in asuspension. (II) Simethicone emulsion was added to the Eudragit Esuspension while stirring using a high shear mixer.

Step 3. Application of the Coating Suspension from Step 2 to Form anAcid Labile Coat Surrounding the Tablet from Step 1b:

Tablets from Step 1b were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 2 was applied to thetablets obtained from Step 1b, using a peristaltic pump and spray gun.The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to form about 40 mg/cm² to about 50 mg/cm² ofthe coat surrounding the tablet.

Step 4. Preparation of a Coating Suspension of the Ingredients of theAlkalinizing Coat:

(I) Water was added into a stainless steel vessel followed by OpadryWhite until no lumps are seen in the resulting suspension. (II) To avortex of this suspension was added magnesium hydroxide until finelydispersed.

Step 5. Application of the Coating Suspension from Step 4 to Form anAlkalinizing Coat Surrounding the Coated Tablet from Step 3:

Tablets from Step 3 were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 4 was applied to thetablets obtained from Step 3, using a peristaltic pump and spray gun.The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to a weight gain of about 50% wt/wt to about70% wt/wt of the coated tablet from Step 3.

Example 22. Tramadol HCl Overdose Resistant (ODR) 50 mg Tablets

Formula for Core Ingredients % w/w Tramadol HCl 12.50 Lactose 57.50Hydroxypropyl 4.00 methylcellulose Microcrystalline cellulose 15.00Starch 1500 10.00 Magnesium stearate 1.00

Formula for Acid Labile Coat* Ingredients % w/w Eudragit E 9.73 SodiumLauryl Sulfate 0.97 Talc 3.40 Stearic Acid 1.46 Simethicone Emulsion 30%2.81 Water 81.63 *1375.64 g of coating suspension was made and appliedto 500 g of tablets

Formula for Alkalinizing Coat* Ingredients % w/w Opadry White 10.00Magnesium Hydroxide 15.18 Aluminium Hydroxide 5.00 Water 69.82 *1000 gof coating suspension was made and applied to 500 g of tablets

Processing Techniques

Step 1a. Preparation of Granules for the Core:

All the ingredients with the exception of the magnesium stearate fromthe core formula were charged into a high shear granulator and dry mixedfor less than 10 minutes. The dry mixed granules were discharged into aPaterson Kelly V-Blender. The magnesium stearate was then added to theV-Blender. The granules were blended for less than 10 minutes.

Step 1b. Preparation of the core (immediate release tablets):

The cores are tablets made from the granules prepared in Step 1a. Arotary press was set-up to produce capsule shaped tablets each weighingabout 400 mg (a Manesty tablet press with 16 stations was used).Granules from Step 1a were charged into a feed hopper and the tablet wasproduced from the double rotary press by applying suitable compressionforce to give tablets of required thickness, hardness and friability.

Step 2. Preparation of a Coating Suspension of the Ingredients of theAcid Labile Coat:

(I) Water was added into a stainless steel vessel followed by sodiumlauryl sulfate until dissolved. To this was added stearic acid followedby Eudragit E and talc, step-by-step, while stirring vigorously with ahigh shear mixer until all ingredients were finely dispersed in asuspension. (II) Simethicone emulsion was added to the Eudragit Esuspension while stirring using a high shear mixer.

Step 3. Application of the Coating Suspension from Step 2 to Form anAcid Labile Coat Surrounding the Tablet from Step 1b:

Tablets from Step 1b were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 2 was applied to thetablets obtained from Step 1b, using a peristaltic pump and spray gun.The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to form about 25 mg/cm² to about 35 mg/cm² ofthe coat surrounding the tablet.

Step 4. Preparation of a Coating Suspension of the Ingredients of theAlkalinizing Coat:

(I) Water was added into a stainless steel vessel followed by OpadryWhite until no lumps are seen in the resulting suspension. (II) To avortex of this suspension was added magnesium hydroxide until finelydispersed.

Step 5. Application of the Coating Suspension from Step 4 to Form anAlkalinizing Coat Surrounding the Coated Tablet from Step 3:

Tablets from Step 3 were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 4 was applied to thetablets obtained from Step 3, using a peristaltic pump and spray gun.The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to a weight gain of about 50% wt/wt to about70% wt/wt of the coated tablet from Step 3.

Example 23. Pregabalin Overdose Resistant (ODR) 50 mg Capsules

Formula for Core (Spheres) Ingredients % w/w Pregabalin 60.00Hydroxypropyl methylcellulose 4.00 Microcrystalline cellulose 35.00 Talc1.00

Formula for Acid Labile Coat* Ingredients % w/w Eudragit E 9.73 SodiumLauryl Sulfate 0.97 Talc 3.40 Stearic Acid 1.46 Simethicone Emulsion 30%2.81 Water 81.63 *1375.64 g of coating suspension was made and appliedto 500 g of spheres

Formula for Alkalinizing Coat* Ingredients % w/w Opadry White 10.00Magnesium Hydroxide 15.18 Aluminium Hydroxide 5.00 Water 69.82 *1000 gof coating suspension was made and applied to 500 g of spheres

Processing Techniques

Step 1a. Preparation of Wet Granules to Make Spheres for the Core:

All the ingredients from the core formula were charged into a high sheargranulator and dry mixed for less than 10 minutes. The dry mixedgranules were wet granulated with water.

Step 1b. Preparation of Spheres for the Core byExtrusion/Spheronization:

The cores are spherical beads made from the wet granules prepared inStep 1a.

An extruder and spheronizer was set-up to produce spherical beads ofpotency 60%. Wet granules from Step 1a were charged into the extruderand extruded. The extrudates were discharged into a spheronizer andspheronised to form spherical beads of between 850 to 1000 microns indiameter. The beads where dried in a conventional oven at 60 degreescentigrade to a loss of drying less than 2.0%.

Step 2. Preparation of a Coating Suspension of the Ingredients of theAcid Labile Coat

(I) Water was added into a stainless steel vessel followed by sodiumlauryl sulfate until dissolved. To this was added stearic acid followedby Eudragit E and talc, step-by-step, while stirring vigorously with ahigh shear mixer until all ingredients were finely dispersed in asuspension. (II) Simethicone emulsion was added to the Eudragit Esuspension while stirring using a high shear mixer.

Step 3. Application of the Coating Suspension from Step 2 to Form a pHSensitive Coat Surrounding the Spheres from Step 1b:

Spheres from Step 1b were charged into a fluid bed coater with a bottomspray (Wurster) assembly. The suspension from Step 2 was applied to thespheres obtained from Step 1b, using a peristaltic pump and spray gun.The suspension was dried as a film onto the spheres, using heated airdrawn through the fluid bed from an inlet fan. A sufficient amount ofthe suspension was applied to form about 15 mg/cm² to about 20 mg/cm² ofthe coat surrounding the spheres.

Step 4. Preparation of a Coating Suspension of the Ingredients of theAlkalinizing Coat:

(I) Water was added into a stainless steel vessel followed by OpadryWhite until no lumps are seen in the resulting suspension. (II) To avortex of this suspension was added magnesium hydroxide until finelydispersed.

Step 5. Application of the Coating Suspension from Step 4 to Form anAlkalinizing Coat Surrounding the Coated Spheres from Step 3:

Spheres from Step 1b were charged into a fluid bed coater with a bottomspray (Wurster) assembly. The suspension from Step 2 was applied to thespheres obtained from Step 1b, using a peristaltic pump and spray gun.The suspension was dried as a film onto the spheres, using heated airdrawn through the fluid bed from an inlet fan. A sufficient amount ofthe suspension was applied to a weight gain of about 40% wt/wt to about50% wt/wt of the coated spheres from Step 3.

Step 6. Encapsulation of Spheres from Step 5 into Hard Gelatin Capsules:

Spheres from Step 5 were filled into hard gelatin capsules. A sufficientamount of the spheres to give 50 mg of Pregabalin per filled capsule wasencapsulated.

Example 24

Similar experiments with respect to the above examples were conductedusing a variety of alkalinizing agent(s) in the alkalinizing coat. Theresults were similar to those obtained with respect to the aboveexamples, wherein dissolution of the unit dosage forms was inverselycorrelated with the number added to an acidic solution.

Example 25. Oxycodone Sustained Action (SA) 80 mg ODR Tablets (EachTablet Contain 60 mg in the Core and 20 mg External to the Core)

Formula for core Ingredients % w/w Oxycodone HCl 30.00 PolyethyleneOxide 50.00 Polyethylene Glycol 16.50 Butylated hydroxytoluene 0.50Eudragit RL 2.00 Magnesium stearate 1.00

Formula for Loading Dose Ingredients % w/w Opadry White 12.63 OxycodoneHCl 2.37 Water 85.00

Formula for Acid labile coat Ingredients % w/w Eudragit E (milled) 59.30Sodium Lauryl sulfate 5.93 Stearic acid (milled) 8.89 Talc 20.75Simethicone 5.13 Water Qs

Formula for Alkalinizing Coat Ingredients % w/w Opadry White 10.00Magnesium Hydroxide 20.18 Water 69.82

Processing Techniques

Step 1a. Preparation of Granules for the Maintenance Dose by Hot MeltExtrusion:

All the ingredients with the exception of the magnesium stearate fromthe core formula were added into a high shear granulator and dry mixedfor less than 10 minutes. The dry mixed granules were discharged into ahopper of a Hot Melt Extruder and gradually fed into the Hot MeltExtruder heated barrel, while mixing by using the rotating screw elementof the extruder. The material was extruded through a die attached at theend of a barrel. The extrudates were milled into granules. The milledgranules were charged into a Paterson Kelly V-Blender. The magnesiumstearate was added into the V-Blender and blended for less than 10minutes.

Step 1b. Preparation of the granules for loading dose by Hot MeltExtrusion:

All the ingredients with the exception of the magnesium stearate andmicrocrystalline cellulose from the maintenance dose formula were addedinto a high shear granulator and dry mixed for less than 10 minutes. Thedry mixed granules were discharged into a hopper of a Hot Melt Extruderand gradually fed into the Hot Melt Extruder heated barrel, while mixingby using the rotating screw element of the extruder. The material wasextruded through a die attached at the end of a barrel. The extrudateswere milled into granules. The milled granules were charged into aPaterson Kelly V-Blender. The magnesium stearate and microcrystallinecellulose were added into the V-Blender and blended for less than 10minutes. The barrel section temperatures of the hot melt extruder aretypically optimized so that the viscosity of the melt is low enough toallow conveying down the barrel and proper mixing, while keepingtemperatures low enough to avoid thermal degradation of the materials;typically about 100 to about 200° C.

Step 1c. Preparation of the core (Extended release tablets):

The cores are tablets made from the granules prepared in Step 1b. Arotary press was set-up to produce capsule shaped tablets each weighingabout 400 mg (a Manesty tablet press with 16 stations was used).Granules from Step 1b were charged into a feed hopper and the tablet wasproduced from the double rotary press by applying suitable compressionforce to give tablets of required thickness, hardness and friability

Step 2. Preparation of a Coating Suspension of the Ingredients for theLoading Dose to be Applied to the Tablet from Step 1c:

(I) Water was added into a stainless steel vessel. (II) Opadry was addedwhile stirring with a propeller mixer until all ingredients are finelydispersed in a suspension. (III) Oxycodone HCl was added to the Opadrywater mixture while stirring using a propeller mixer.

Step 3. Application of the Coating Suspension from Step 2 to Form Partof the Loading Dose Surrounding the Tablet from Step 1c:

Tablets from step 2 were charged into a rotating drum of a side ventedautomated Tablet coater (Rama Cota Tablet Film Coater was used). Thesuspension from Step 3 was applied to the tablets obtained from Step 2,using a peristaltic pump and spray gun. The suspension was dried as afilm onto the tablets, using heated air drawn through the tablet bedfrom an inlet fan. The suspension is applied to form a coat surroundingthe tablet.

Step 4. Preparation of Acid Labile Coating Suspension to be Applied tothe Tablet from Step 3:

(I) Water was added into a stainless steel vessel followed by Sodiumlauryl sulfate and stearic acid, step-by-step, while stirring vigorouslywith a high shear mixer until all ingredients are dissolved. (II)Eudragit E was added, step-by-step, while stirring vigorously with ahigh shear mixer until all ingredients were dissolved. (III) Talc wasadded, followed by simethicone while stirring using a high shear mixeruntil finely dispersed in the solution.

Step 5. Application of a Coating Suspension from Step 4 to Form an AcidLabile Coat Surrounding the Tablet from Step 3:

Tablets from step 3 were charged into the rotating drum of a side ventedautomated Tablet coater (Rama Cota Tablet Film Coater was used). Thesuspension from Step 4 was applied to the tablets obtained from Step 3,using a peristaltic pump and spray gun. The suspension was dried as afilm onto the tablets, using heated air drawn through the tablet bedfrom an inlet fan. A sufficient amount of the suspension was applied toform about 10 mg/cm² to about 20 mg/cm² of the coat surrounding thetablet.

Step 6. Preparation of a Coating Suspension of the Ingredients of theAlkalinizing Coat:

(I) Water was added into a stainless steel vessel followed by OpadryWhite until no lumps are seen in the resulting suspension. (II) To avortex of this suspension was added magnesium hydroxide until finelydispersed.

Step 7. Application of the Coating Suspension from Step 6 to Form anAlkalinizing Coat Surrounding the Coated Tablets from Step 5:

Tablets from Step 5 were charged into the rotating drum of a side ventedautomated Tablet coater (Rama Cota Tablet Film Coater was used). Thesuspension from Step 6 was applied to the tablets obtained from Step 5,using a peristaltic pump and spray gun. The suspension was dried as afilm onto the tablets, using heated air drawn through the tablet bedfrom an inlet fan. A sufficient amount of the suspension was applied toform coat containing about 30 mg to 150 mg of magnesium hydroxide percoated tablet.

Example 26. Oxycodone Sustained Action (SA) 80 mg ODR Tablets (EachTablet Contain 60 mg in the Core and 20 mg External to the Core)

Formula for core Ingredients % w/w Oxycodone HCl 7.50 Polyethylene Oxide43.71 Lactose 22.79 Crospovidone 10.00 Microcrystalline cellulose 10.50Eudragit RL 5.00 Magnesium stearate 0.50

Formula for Loading Dose Ingredients % w/w Opadry White 12.63 OxycodoneHCl 2.37 Water 85.00

Formula for Acid labile coat Ingredients % w/w Eudragit E (milled) 59.30Sodium Lauryl sulfate 5.93 Stearic acid (milled) 8.89 Talc 20.75Simethicone 5.13 Water Qs

Formula for Alkalinizing Coat Ingredients % w/w Opadry White 10.00Magnesium Hydroxide 20.18 Water 69.82

Processing Techniques

Step 1a. Preparation of Granules for the Core:

All the ingredients with the exception of the magnesium stearate fromthe core formula were charged into a high shear granulator and dry mixedfor less than 10 minutes. The dry mixed granules were discharged into aPaterson Kelly V-Blender. The magnesium stearate was then added to theV-Blender. The granules were blended for less than 10 minutes.

Step 1b. Preparation of the Core (Extended Release Tablets):

The cores are tablets made from the granules prepared in Step 1a. Arotary press was set-up to produce capsule shaped tablets each weighingabout 400 mg (a Manesty tablet press with 16 stations was used).Granules from Step 1a were charged into a feed hopper and the tablet wasproduced from the double rotary press by applying suitable compressionforce to give tablets of required thickness, hardness and friability.

Step 2. Preparation of a Coating Suspension of the Ingredients for theLoading Dose to be Applied to the Tablet from Step 1b:

(I) Water was added into a stainless steel vessel. (II) Opadry was addedwhile stirring with a propeller mixer until all ingredients are finelydispersed in a suspension. (III) Oxycodone HCl was added to the Opadrywater mixture while stirring using a propeller mixer.

Step 3. Application of the Coating Suspension from Step 2 to Form Partof the Loading Dose Surrounding the Tablet from Step 1b:

Tablets from step 1b were charged into a rotating drum of a side ventedautomated Tablet coater (Rama Cota Tablet Film Coater was used). Thesuspension from Step 2 was applied to the tablets obtained from Step 1b,using a peristaltic pump and spray gun.

The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. The suspension isapplied to form a coat surrounding the tablet.

Step 4. Preparation of Acid Labile Coating Suspension to be Applied tothe Tablet from Step 3:

(I) Water was added into a stainless steel vessel followed by Sodiumlauryl sulfate and stearic acid, step-by-step, while stirring vigorouslywith a high shear mixer until all ingredients are dissolved. (II)Eudragit E was added, step-by-step, while stirring vigorously with ahigh shear mixer until all ingredients were dissolved. (III) Talc wasadded, followed by simethicone while stirring using a high shear mixeruntil finely dispersed in the solution.

Step 5. Application of a Coating Suspension from Step 4 to Form an AcidLabile Coat Surrounding the Tablet from Step 3:

Tablets from step 3 were charged into the rotating drum of a side ventedautomated Tablet coater (Rama Cota Tablet Film Coater was used). Thesuspension from Step 4 was applied to the tablets obtained from Step 3,using a peristaltic pump and spray gun.

The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to form about 10 mg/cm² to about 20 mg/cm² ofthe coat surrounding the tablet.

Step 6. Preparation of a Coating Suspension of the Ingredients of theAlkalinizing Coat:

(I) Water was added into a stainless steel vessel followed by OpadryWhite until no lumps are seen in the resulting suspension. (II) To avortex of this suspension was added magnesium hydroxide until finelydispersed.

Step 7. Application of the Coating Suspension from Step 6 to Form anAlkalinizing Coat Surrounding the Coated Tablets from Step 5:

Tablets from Step 5 were charged into the rotating drum of a side ventedautomated Tablet coater (Rama Cota Tablet Film Coater was used). Thesuspension from Step 6 was applied to the tablets obtained from Step 5,using a peristaltic pump and spray gun.

The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to form coat containing about 70 mg to 150 mgof magnesium hydroxide per coated tablet.

Example 27. Dissolution Test of Coated Tablets from Example 26

Table 17 and FIG. 17 below show the amount of oxycodone released inpercent over a 24 hour period when one tablet or multiple tablets aresubjected to dissolution in 0.01N HCl solution using USP Paddle at 100rpm. The results show that the more unit dosage forms there are, theless the amount of drug released. Less than 1% of the drug is releasedeven after 5 hours when 2 or more tablets are present, and less than 5%of drug is released after 12 hours for 4 tablets, 6 tablets, 8 tablets,10 or more tablets. It is even more dramatic for 20 tablets where lessthan 5% is released in 19 hours with only 8% of the drug being releasedin 24 hours.

TABLE.17 Dissolution of various quantities of intact Rexista OxyC 80 mgTablets (ODRA type1) One tablet of Rexista OxyC 80 mg (ODRA type1):Media 0.01N HCl, 37° C., Paddle Speed 100 RPM Amounts released (%)Rexista OxyC Rexista OxyC Rexista OxyC Rexista OxyC Rexista OxyC RexistaOxyC Time 80 mg × 1 tablet 80 mg × 2 tablets 80 mg × 4 tablets 80 mg × 6tablets 80 mg × 10 tablets 80 mg × 20 tablets (hrs) (80 mg) (160 mg)(320 mg) (480 mg) (800 mg) (1600 mg) 0 0 0 0 0 0 0 1 33.5 0 0 0 0 0 243.463 0 0 0 0 0 3 50.9559789 0 0 0.0438 0.0288 0 4 57.2340725 0.2813 00.0793 0.0788 0.0219 5 62.6811714 0.7071 0 0.2233 0.2478 0.0838 665.8323101 1.1842 0.1219 0.5177 0.5711 0.1828 7 67.3656349 2.2628 0.34410.986 1.0191 0.3215 8 69.931139 3.6072 0.7514 1.6223 1.5772 0.5006 975.8295047 5.3557 1.3537 2.4002 2.2095 0.7328 10 78.3210006 7.09712.1454 3.2596 2.995 0.9775 11 81.2326784 9.1001 3.127 4.1883 3.90791.0911 12 83.4283614 11.078 4.2178 5.2908 3.9974 1.3457 13 84.518356213.475 5.5496 5.9279 4.6872 1.5567 14 85.8117431 13.472 10.129 9.63374.2729 1.7634 15 87.7341677 16.495 11.623 11.484 5.141 1.9826 1689.1501124 19.765 16.316 15.555 7.5581 2.2368 17 90.7205050 23.12 18.94817.335 8.1241 2.4731 18 91.4208464 26.717 21.335 18.635 8.8068 2.7214 1991.5859017 30.319 24.08 19.01 10.804 2.9568 20 91.3139805 34.445 26.60822.362 10.765 6.0216 21 91.3911942 32.696 19.607 18.551 14.782 6.6043 2292.4465798 35.03 21.3 20.303 15.905 7.0914 23 93.8800000 37.846 23.36622.083 16.727 6.7012 24 94.9274496 41.646 24.308 24.044 17.764 7.9217

Example 28. Preparation of Pantoprazole Overdose Resistant (ODR) 10 mgTablets

Formula for Core Ingredients % w/w Pantoprazole sodium 22.17 Lactose20.11 Polyvinyl pyrolidone 0.65 Crospovidone 10.00 Sodium carbonate41.15 Calcium stearate 15.00 Sodium lauryl sulphate 4.93

Formula for seal Coat Ingredients % w/w Opadry White 11.25 MagnesiumHydroxide 3.75 Water 85.00

Formula for Alkaline Labile Enteric Coat Ingredients % w/w Eudragit L76.33 Triethyl citrate 9.16 Glycerol monostaerate 14.50 Water qs

Formula for Acidifying Coat Ingredients % w/w Opadry White 15.00 Citricacid 3.50 Fumaric acid 3.50 Water 79.00

Formula for Alkaline Labile Enteric Coat Ingredients % w/w Eudragit L76.33 Triethyl citrate 9.16 Glycerol monostaerate 14.50 Water qs

Processing Techniques

Step 1a. Preparation of Granules for the Core:

All the ingredients with the exception of the polyvinyl pyrolidone andcalcium stearate from the core formula were charged into a high sheargranulator and dry mixed for less than 5 minutes and wet granulatedusing 2% solution of polyvinyl pyrolidone for another 2 minutes. The wetgranules were dried in a fluid bed dryer to a loss of drying of lessthan 2% The dried granules were discharged into a Paterson KellyV-Blender. The calcium stearate was then added to the V-Blender. Thegranules were blended for less than 10 minutes.

Step 1b. Preparation of the Core (Immediate Release Tablets):

The cores are tablets made from the granules prepared in Step 1a. Arotary press was set-up to produce capsule shaped tablets each weighingabout 200 mg (a Manesty tablet press with 16 stations was used).Granules from Step 1a were charged into a feed hopper and the tablet wasproduced from the double rotary press by applying suitable compressionforce to give tablets of required thickness, hardness and friability.

Step 2. Preparation of a Coating Suspension of the Ingredients of theSeal Coat:

(I) Water was added into a stainless steel vessel followed by OpadryWhite until no lumps are seen in the resulting suspension. (II) To avortex of this suspension was added magnesium hydroxide until finelydispersed.

Step 3. Application of the Coating Suspension from Step 2 to Form a SealCoat Surrounding the Tablet Cores from Step 1b:

Tablets from Step 1b were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 2 was applied to thetablet cores obtained from Step 1b, using a peristaltic pump and spraygun. The suspension was dried as a film onto the tablets, using heatedair drawn through the tablet bed from an inlet fan.

A sufficient amount of the suspension was applied to a weight gain ofabout 8 to 15%

Step 4. Preparation of a Coating Suspension of the Ingredients of theAlkaline Labile Enteric Coat:

(I) Water was added into a stainless steel vessel followed by sodiumlauryl sulfate until dissolved. To this was gradually added Eudragit Las and L30D-55 dispersion, while stirring vigorously with a low shearmixer until all ingredients were finely dispersed in a suspension. (II)Glycerol monostearate was added to the Eudragit dispersion whilestirring using a low shear mixer.

Step 5. Application of the Coating Suspension from Step 4 to Form anAlkaline Labile or Enteric Coat Surrounding the Tablets from Step 3:

Tablets from Step 3 were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 4 was applied to thetablets obtained from Step 3, using a peristaltic pump and spray gun.The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to form about 5 mg/cm² to about 12 mg/cm² ofthe coat surrounding the tablet.

Step 6. Preparation of a Coating Suspension of the Ingredients of theAcidifying Coat:

(I) Water was added into a stainless steel vessel followed by OpadryWhite until no lumps are seen in the resulting suspension. (II) To avortex of this suspension was added citric acid followed by fumaric aciduntil finely dispersed.

Step 7. Application of the Coating Suspension from Step 6 to Form anAcidifying Coat Surrounding the Coated Tablet from Step 5:

Tablets from Step 5 were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 6 was applied to thetablets obtained from Step 5, using a peristaltic pump and spray gun.The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to a weight gain of about 30% wt/wt to about70% wt/wt of the coated tablet from Step 5.

Step 8. Preparation of a Coating Suspension of the Ingredients of theAlkaline Labile Enteric Coat:

(I) Water was added into a stainless steel vessel followed by sodiumlauryl sulfate until dissolved. To this was gradually added Eudragit Las and L30D-55 dispersion, while stirring vigorously with a low shearmixer until all ingredients were finely dispersed in a suspension. (II)Glycerol monostearate was added to the Eudragit dispersion whilestirring using a low shear mixer.

Step 9. Application of the Coating Suspension from Step 8 to Form anAlkaline Labile or Enteric Coat Surrounding the Tablets from Step 7:

Tablets from Step 7 were charged into a rotating drum of a side ventedautomated tablet coater. The suspension from Step 8 was applied to thetablets obtained from Step 7, using a peristaltic pump and spray gun.The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to form about 3 mg/cm² to about 12 mg/cm² ofthe coat surrounding the tablet.

Example 29. Oxycodone Sustained Action (SA) 80 mg ODR Tablets (EachTablet Contain 70 mg in the Core and 10 mg External to the Core)

Formula for core Ingredients % w/w Oxycodone HCl 18.34 PolyethyleneOxide 65.00 Aluminum lake Blue#1 4.00 Crospovidone 2.00 Microcrystallinecellulose 11.66 Eudragit RL 2.00 Magnesium stearate 0.50

Formula for Loading Dose Ingredients % w/w Opadry White 13.09 OxycodoneHCl 9.53 Water 77.38

Formula for Acid labile coat Ingredients % w/w Eudragit E (milled) 9.73Sodium Lauryl sulfate 0.974 Stearic acid (milled) 1.46 Talc 3.40Simethicone 0.84 Water QS

Formula for Alkalinizing Coat Ingredients % w/w Opadry White 16.132Magnesium Hydroxide 16.592 Water 67.276

Processing Techniques

Step 1a. Preparation of Granules for the Core:

All the ingredients with the exception of the magnesium stearate fromthe core formula were charged into a high shear granulator and dry mixedfor less than 10 minutes. The dry mixed granules were discharged into aPaterson Kelly V-Blender. The magnesium stearate was then added to theV-Blender. The granules were blended for less than 10 minutes.

Step 1b. Preparation of the Core (Extended Release Tablets):

The cores are tablets made from the granules prepared in Step 1a. Arotary press was set-up to produce capsule shaped tablets each weighingabout 400 mg (a Manesty tablet press with 16 stations was used).Granules from Step 1a were charged into a feed hopper and the tablet wasproduced from the double rotary press by applying suitable compressionforce to give tablets of required thickness, hardness and friability.

Step 2. Preparation of a Coating Suspension of the Ingredients for theLoading Dose to be Applied to the Tablet from Step 1b:

(I) Water was added into a stainless steel vessel. (II) Opadry was addedwhile stirring with a propeller mixer until all ingredients are finelydispersed in a suspension. (III) Oxycodone HCl was added to the Opadrywater mixture while stirring using a propeller mixer.

Step 3. Application of the Coating Suspension from Step 2 to Form Partof the Loading Dose Surrounding the Tablet from Step 1b:

Tablets from step 1b were charged into a rotating drum of a side ventedautomated Tablet coater (Rama Cota Tablet Film Coater was used). Thesuspension from Step 2 was applied to the tablets obtained from Step 1b,using a peristaltic pump and spray gun.

The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. The suspension isapplied to form a coat surrounding the tablet.

Step 4. Preparation of Acid Labile Coating Suspension to be Applied tothe Tablet from Step 3:

(I) Water was added into a stainless steel vessel followed by Sodiumlauryl sulfate and stearic acid, step-by-step, while stirring vigorouslywith a high shear mixer until all ingredients are dissolved. (II)Eudragit E was added, step-by-step, while stirring vigorously with ahigh shear mixer until all ingredients were dissolved. (III) Talc wasadded, followed by simethicone while stirring using a high shear mixeruntil finely dispersed in the solution.

Step 5. Application of a Coating Suspension from Step 4 to Form an AcidLabile Coat Surrounding the Tablet from Step 3:

Tablets from step 3 were charged into the rotating drum of a side ventedautomated Tablet coater (Rama Cota Tablet Film Coater was used). Thesuspension from Step 4 was applied to the tablets obtained from Step 3,using a peristaltic pump and spray gun.

The suspension was dried as a film onto the tablets, using heated airdrawn through the tablet bed from an inlet fan. A sufficient amount ofthe suspension was applied to form about 4 mg/cm² to about 20 mg/cm² ofthe coat surrounding the tablet.

Step 6. Preparation of a Coating Suspension of the Ingredients of theAlkalinizing Coat:

(I) Water was added into a stainless steel vessel followed by OpadryWhite until no lumps are seen in the resulting suspension. (II) To avortex of this suspension was added magnesium hydroxide until finelydispersed.

Step 7. Application of the Coating Suspension from Step 6 to Form anAlkalinizing Coat Surrounding the Coated Tablets from Step 5:

Tablets from Step 5 were charged into the rotating drum of a side ventedautomated Tablet coater (Rama Cota Tablet Film Coater was used). Thesuspension from Step 6 was applied to the tablets obtained from Step 5,using a peristaltic pump and spray gun. The suspension was dried as afilm onto the tablets, using heated air drawn through the tablet bedfrom an inlet fan. A sufficient amount of the suspension was applied toform coat containing about 20 mg to 24 mg of magnesium hydroxide percoated tablet.

FIGS. 18 to 26 below show the results of the various tests for thisexample.

Example 30. Same as Example 29 Except that Each Tablet Contain 52.5 mgin the Core and 7.5 mg External to the Core

Formula for core Ingredients % w/w Oxycodone HCl 13.755 PolyethyleneOxide 61.00 Aluminum lake Blue#1 4.00 Crospovidone 4.00 Microcrystallinecellulose 14.24 Eudragit RL 2.00 Magnesium stearate 1.00

Formula for Loading Dose Ingredients % w/w Opadry White 12.73 OxycodoneHCl 7.86 Water 79.41

Example 31. Same as Example 29 Except that Each Tablet Contain 7.5 mg inthe Core and 2.5 mg External to the Core

Formula for core Ingredients % w/w Oxycodone HCl 1.973 PolyethyleneOxide 80.21 Aluminum lake Blue#1 4.00 Crospovidone 5.00 Microcrystallinecellulose 4.00 Eudragit RL 2.38 Magnesium stearate 0.44

Formula for Loading Dose Ingredients % w/w Opadry White 12.63 OxycodoneHCl 2.37 Water 85.00

Example 32. Same as Example 29 Except that Each Tablet Contain 8.75 mgin the Core and 1.25 mg External to the Core

Formula for core Ingredients % w/w Oxycodone HCl 2.822 PolyethyleneOxide 67.69 Aluminum lake Blue#1 6.00 Crospovidone 2.00 Microcrystallinecellulose 18.99 Eudragit RL 2.00 Magnesium stearate 0.50

Formula for Loading Dose Ingredients % w/w Opadry White 15.091 OxycodoneHCl 1.612 Water 83.297

Example 33. Same as Example 29 Except that Each Tablet Contain 13.125 mgin the Core and 1.875 mg External to the Core

Formula for core Ingredients % w/w Oxycodone HCl 4.232 PolyethyleneOxide 73.69 Aluminum lake Blue#1 4.00 Crospovidone 2.00 Microcrystallinecellulose 13.58 Eudragit RL 2.00 Magnesium stearate 0.50

Formula for Loading Dose Ingredients % w/w Opadry White 13.091 OxycodoneHCl 2.418 Water 84.490

Example 34. Same as Example 29 Except that Each Tablet ContainOxymorphone HCl as Active Substance i.e., 35 mg in the Core and 5 mgExternal to the Core

Formula for core Ingredients % w/w Oxymorphone HCl 11.507 PolyethyleneOxide 64.27 Aluminum lake Blue#1 4.00 Crospovidone 2.00 Microcrystallinecellulose 15.72 Eudragit RL 2.00 Magnesium stearate 0.50

Formula for Loading Dose Ingredients % w/w Opadry White 14.216 OxycodoneHCl 6.575 Water 79.461

1-64. (canceled)
 65. A method of inhibiting or preventing drug overdosein a patient, comprising administering to the patient a unit doseformulation comprising: at least one active substance, wherein releaseof said at least one active substance is inhibited when the number ofunit dosage forms ingested exceeds a predetermined number; at least oneactuator; and at least one regulator surrounding said at least oneactive substance and said at least one actuator, whereby when the unitdose formulation is exposed to a fluid media having a process variable,and a predetermined threshold is established for the process variable,said at least one regulator is capable of adjusting the variable tocontrol the release of said at least one active substance via said atleast one actuator, when the number of unit dosage forms exceeds thepredetermined number.
 66. A method according to claim 65, wherein saidat least one regulator is present in an amount sufficient to raise thevariable above the threshold, such that dissolution of said at least oneactuator and release of said at least one active substance via theactuator is inhibited when the number of unit dosage forms ingestedexceeds the predetermined number.
 67. A method according to claim 65,wherein said at least one regulator is present in an amount sufficientto decrease the variable below the threshold, such that dissolution ofsaid at least one actuator and release of said at least one activesubstance via the actuator is inhibited when the number of unit dosageforms ingested exceeds the predetermined number.
 68. A method accordingto claim 65, wherein the fluid media is an acidic media.
 69. A methodaccording to claim 65, wherein the fluid media is a basic media.
 70. Amethod according to claim 65, wherein the variable is pH.
 71. A methodaccording to claim 65, wherein the regulator and/or actuator is aphysical/chemical barrier.
 72. A method according to claim 65, whereinthe regulator is a pH independent barrier and the actuator is a pHdependent barrier.
 73. A method according to claim 65, wherein said atleast one regulator comprises at least one alkalinizing agent.
 74. Amethod according to claim 65, wherein said at least one alkalinizingagent is selected from the group consisting of alkaline earth metalsalts, alkali metal salts, aluminum salts, amino acids, and amino acidderivatives.
 75. A method according to claim 74, wherein said at leastone alkalinizing agent is selected from the group consisting ofmagnesium hydroxide, magnesium trisilicate, aluminum hydroxide,magnesium oxide, calcium carbonate, sodium bicarbonate, sodium citrate,sodium carbonate, sodium acetate, magnesium carbonate, L-arginine,meglumine, and combinations thereof.
 76. A method according to claim 75,wherein said at least one alkalinizing agent is magnesium hydroxide. 77.A method according to claim 65, wherein said at least one regulatorcomprises at least one acidifying agent.
 78. A method according to claim77, wherein said at least one regulator is selected from the groupconsisting of an inorganic acid, an organic acid, and combinationsthereof.
 79. A method according to claim 78, wherein said at least oneacidifying agent is selected from the group consisting of hydrochloricacid, sulfuric acid, nitric acid, lactic acid, phosphoric acid, citricacid, malic acid, fumaric acid, stearic acid, tartaric acid, boric acid,borax, benzoic acid, and combinations thereof.
 80. A method according toclaim 79, wherein said at least one acidifying agent is fumaric acidand/or citric acid.
 81. A method according to claim 65, wherein said atleast one actuator comprises at least one acid labile substance.
 82. Amethod according to claim 81, wherein said at least one acid labilesubstance is selected from the group consisting of sulfonamide-basedpolymers and copolymers, amine functional polymers and copolymers,polysaccharides, poly(vinylpyrrolidone-co-dimethylmaleic anhydride)(PVD), dimethylaminoethyl methacrylate copolymers, and combinationsthereof.
 83. A method according to claim 82, wherein the aminefunctional polymers is selected from the group consisting of polyvinylpyridine polymers and copolymers.
 84. A method according to claim 82,wherein the polysaccharides is chitosan.
 85. A method according to claim82, wherein the dimethylaminoethyl methacrylate copolymers are selectedfrom the group consisting of 2-propenoic acid, 2-methyl-, butyl ester,polymer with 2-(dimethylamino)ethyl 2-methyl-2-propenoate and methyl2-methyl-2-propenoate (Eudragit™ E, CAS Registry Number 24938-16-7),2-propenoic acid, 2-methyl-, butyl ester, polymer with2-(dimethylamino)ethyl 2-methyl-2-propenoate and methyl2-methyl-2-propenoate interpolyelectrolyte complex (Eudragit™ Einterpolyelectrolyte complex), 2-propenoic acid, 2-methyl-, butyl ester,polymer with 2-(dimethylamino)ethyl 2-methyl-2-propenoate and methyl2-methyl-2-propenoate polyamopholyte complex (Eudragit™ E polyamopholytecomplex), 2-propenoic acid, 2-methyl-, butyl ester, polymer with2-(dimethylamino)ethyl 2-methyl-2-propenoate and methyl2-methyl-2-propenoate complex with methacrylic acid and methylmethacrylate copolymer (1:2) (Eudragit™ E interpolyelectrolyte complexwith Eudragit™ L), methacrylic acid and methyl methacrylate copolymer(1:2) (Eudragit™ S), derivatives thereof, and combinations thereof. 86.A method according to claim 85, wherein said at least one acid labilesubstance comprises 2-propenoic acid, 2-methyl-, butyl ester, polymerwith 2-(dimethylamino)ethyl 2-methyl-2-propenoate and methyl2-methyl-2-propenoate (Eudragit™ E, CAS Registry Number 24938-16-7). 87.A method according to claim 65, wherein said at least one actuatorcomprises at least one base labile substance.
 88. A method according toclaim 87, wherein said at least one base labile substance is selectedfrom the group consisting of pharmaceutically acceptable ethers, esters,ketones, epoxies, polyamides, polysiloxanes, enteric polymers, anioniccopolymers based on methacrylic acid and methyl methacrylate, andcombinations thereof.
 89. A method according to claim 88, wherein saidat least one base labile substance comprises at least one entericpolymer.
 90. A method according to claim 89, wherein said at least oneenteric polymer is methacrylic acid and methyl methacrylate copolymer(1:1) (Eudragit™ L) or methacrylic acid and methyl methacrylatecopolymer (1:2) (Eudragit™ S).
 91. A method according to claim 65,wherein dissolution of said at least one actuator and release of said atleast one active substance is reduced upon dissolution of a thresholdamount of said at least one regulator.
 92. A method according to claim65, wherein dissolution of said at least one actuator and release ofsaid at least one active substance decreases in the presence ofincreasing concentrations of at least one regulator.
 93. A methodaccording to claim 65, wherein the rate of dissolution of said at leastone actuator is inversely proportional to the number of unit doseformulations ingested.
 94. A method according to claim 65, wherein, whenthe number of unit dosage forms ingested exceeds a predetermined number,said at least one regulator increases the pH to inhibit dissolution ofsaid at least one actuator and inhibit release of said at least oneactive substance.
 95. A method according to claim 65, wherein, when thenumber of unit dosage forms ingested exceeds a predetermined number,said at least one regulator decreases the pH to inhibit dissolution ofsaid at least one actuator and inhibit release of said at least oneactive substance.
 96. A method according to claim 65, wherein thepredetermined number is less than
 20. 97. A method according to claim96, wherein the predetermined number is 1, 2, 3, 4, or
 5. 98. A methodaccording to claim 96, wherein the predetermined number is 1 or
 2. 99. Amethod according to claim 65, wherein, further comprising at least oneagent selected from the group consisting of an abuse deterrent coloringagent; a controlled release agent; a viscosity imparting agent; agelling agent; polyethylene oxide; crospovidone;N,N-dimethylmethanamine; 2-methylprop-2-enoic acid (Eudragit™ RL CASRegistry No. 51822-44-7); ethyl prop-2-enoate; methyl2-methylprop-2-enoate;trimethyl-[2-(2-methylprop-2-enoyloxy)ethyl]azanium chloride (Eudragit™RS CAS Registry No. 39316-06-8), and combinations thereof.
 100. A methodaccording to claim 65, wherein, further comprising at least one abusedeterrent coloring agent.
 101. A method according to claim 99, whereinsaid at least one abuse deterrent coloring agent is brilliant blue. 102.A method according to claim 99, wherein said at least one abusedeterrent coloring agent is Aluminum Lake Blue#1.
 103. A methodaccording to claim 65, further comprising at least one agent selectedfrom the group consisting of a chewing discouraging agent, a lickingdiscouraging agent, an insufflation discouraging agent, a snortingdiscouraging agent, an inhalation discouraging agent, and combinationsthereof.
 104. A method according to claim 103, wherein the inhalationdiscouraging agent is selected from the group consisting of a coloringagent, a tussigenic agent, an irritant, and combinations thereof.
 105. Amethod according to claim 65, wherein said at least one active substanceis at least one addictive substance.
 106. A method according to claim65, wherein said at least one active substance is at least one opioidagonist and/or at least one narcotic analgesic.
 107. A method accordingto claim 65, wherein said at least one active substance has an analgesicceiling effect.
 108. A method according to claim 65, in the form of abead, tablet, capsule, granule, and/or pellet.
 109. A method accordingto claim 65, wherein said at least one active substance is in an amountof from about 0.1 mg to about 1000 mg; said at least one actuator is inan amount of from about 0.5 mg to about 500 mg; and/or said at least oneregulator is in an amount of from about 0.5 mg to about 500 mg.
 110. Amethod according to claim 65, wherein said at least one actuator ispresent in an amount of from 0.5 mg/cm² to 200 mg/cm² or from 1 mg/cm²to 100 mg/cm² or from 2 mg/cm² to 150 mg/cm² or from about 4 mg/cm² toabout 100 mg/cm² or from 8 mg/cm² to 50 mg/cm².
 111. A method accordingto claim 65, wherein said at least one actuator is used in an amountthat yields from about 1% to about 200% weight gain, from about 1% toabout 70% or from about 1% to about 50% weight gain based on the weightof the formulation.
 112. A method according to claim 65, wherein said atleast one regulator is used in an amount that yields from about 1% toabout 200% weight gain, from about 5% to about 80%, from about 1% toabout 70% weight gain, from about 1% to about 50% or from about 5% toabout 50% weight gain based on the weight of the formulation.
 113. Amethod according to claim 65, wherein release of said at least oneactive substance is a lag time, delayed release, no release orinsignificant release of said at least one active substance.
 114. Amethod according to claim 65 wherein at least one regulatorsubstantially or completely surrounds said at least one active substanceand said at least one actuator.